What Is Known
- Pancreatitis is a rare systemic lupus erythematosus manifestation.
- This involvement has been limited to case reports or case series in patients with childhood-onset systemic lupus erythematosus.
- The International Study Group of Pediatric Pancreatitis proposed definitions to standardize pancreatitis in children.
What Is New
- This was the first study phenotyping pancreatitis according to the International Study Group of Pediatric Pancreatitis-standardized definitions in childhood-onset systemic lupus erythematosus.
- This multicenter study evidenced a predominance of acute subtype.
- Pancreatitis was associated with present glucocorticoid use and active severe disease.
Childhood-onset systemic lupus erythematosus (cSLE) is a rare chronic autoimmune disease characterized by the involvement of various organs and systems, such as pancreas. Pancreatitis is an uncommon and potentially life-threatening cSLE manifestation (1–10).
Of note, this involvement has been attributed to disease activity or drug therapy in adult-SLE (3–7) and cSLE populations (3,8–10). In the latter group, data, however, are limited to case reports and case series in the pediatric population.
The International Study Group of Pediatric Pancreatitis (INSPPIRE) proposed standardized definitions and developed diagnostic algorithms to evaluate and manage pediatric pancreatitis (11). There are no studies, however, using these new definitions in a large population of childhood lupus patients.
Therefore, the objective of the present multicenter study was to systematically classify pancreatitis in patients with cSLE according to the INSPPIRE definitions and determine the overall prevalence, clinical features, laboratory, and outcomes of the first episode.
Study Design and Patients
This is a retrospective multicenter cohort study including 1017 patients with cSLE studied in 10 pediatric rheumatology tertiary referral services in São Paulo state, Brazil. All of the patients fulfilled the American College of Rheumatology (ACR) criteria (12), with disease onset before 18 years of age (13) and present age up to 25 years. One hundred sixty-five patients were excluded owing to incomplete medical charts (n = 96), undifferentiated connective tissue disorder with 3 or fewer ACR criteria (n = 43), isolated cutaneous lupus erythematosus (n = 11), neonatal lupus erythematosus (n = 8), drug-induced lupus (n = 5), and other autoimmune diseases (n = 2). The remaining 852 patients with cSLE comprised the study group.
A meeting of investigators was held for this study in São Paulo city to define the protocol according to the clinical parameters definitions, disease activity and damage tools scoring, and outcome parameters. Data collection training was conducted locally in each of the centers, using the same specific database. Discrepancies were sorted out by 1 or more rounds of queries to check for accuracy. Data were collected between November 2012 and October 2014. Patient's medical charts were carefully reviewed according to an extensive standardized protocol for demographic data, clinical features, laboratory findings, treatments, outcomes, and pancreatitis characteristics.
Pediatric pancreatitis was defined according to the INSPPIRE definitions (11). Acute pancreatitis (AP) was diagnosed by the presence of at least 2 of 3 features: abdominal pain or vomiting, serum levels of pancreatic amylase and/or lipase at least 3 times greater than the upper limit of normal, and imaging findings characteristics of AP on abdominal ultrasound or computed tomography (CT) (11,14,15). Severe pancreatitis was defined as multiorgan dysfunction, pancreatic necrosis, or death (11). Acute recurrent pancreatitis required at least 2 separate episodes of AP with complete resolution of pain or complete normalization serum pancreatic enzyme levels, before the subsequent episode of AP. Chronic pancreatitis required at least one of the following: abdominal pain and radiographic abnormalities of chronic pancreatic damage, evidence of exocrine and/or endocrine pancreatic insufficiency, and suggestive pancreatic imaging abnormalities (11).
Demographic Data, Clinical Evaluation, Disease Activity, Disease Damage, and Drug Therapy
Demographic data included gender, ethnicity, present age, age at cSLE onset, and disease duration. SLE clinical manifestations were defined as constitutional symptoms (fever and weight loss), involvement of the reticuloendothelial system (adenomegaly, hepatomegaly, and splenomegaly), mucocutaneous lesions (malar or discoid rash, photosensitivity, nasal or oral ulcers, vasculitis, and alopecia), musculoskeletal involvement (arthritis and myositis), serositis (pleuritis and pericarditis), nephritis (proteinuria ≥ 0.5 g/24 hours, presence of cellular casts, persistent hematuria ≥ 5 red blood cells per high power field and/or persistent leukocituria ≥ 5 leukocytes per high-power field), hematologic abnormalities (autoimmune hemolytic anemia, leukopenia [white blood cell count <4000/mm3], lymphopenia [lymphocytes count <1500/mm3], and thrombocytopenia [platelet count <100,000/mm3] on 2 or more occasions in the absence of drugs or infection). Neuropsychiatric lupus included 19 syndromes according to ACR classification criteria (16). Antiphospholipid syndrome was diagnosed according to the presence of arterial and/or venous thrombosis and anti-phospholipid antibodies (17).
High blood pressure was defined as systolic and/or diastolic blood pressures ≥ 95th percentile for gender, age, and height on ≥ 3 occasions (18). Acute kidney injury (AKI) was determined by sudden increase in serum creatinine ≥ 2 mg/dL (19) or by modified Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease criteria (20). Chronic renal disease was defined as structural or function abnormalities of the kidney for =3 months (with or without decreased glomerular filtration rate) or glomerular filtration rate < 60 mL/minute/1.73 m2 for ≥ 3 months (21).
Laboratory assessment included erythrocyte sedimentation rate , C-reactive protein, complete blood cell count, serum urea and creatinine, urinalysis, and 24-hour urine protein excretion. Complement levels (CH50, C3, and C4), anti-double-stranded DNA, immunoglobulin G and immunoglobulin M anti-cardiolipin antibodies were carried out at each center. The cutoff values were considered abnormal according to kit manufacturer. Lupus anticoagulant was detected according to the guidelines of the International Society on Thrombosis and Hemostasis (22). SLE disease activity and cumulative damage were scored through the SLE Disease Activity Index 2000 (23) and the Systemic Lupus International Collaborating Clinics/ACR-Damage Index (24), respectively.
Present drug treatment data (prednisone, intravenous methylprednisolone, chloroquine diphosphate, hydroxychloroquine sulfate, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, intravenous cyclophosphamide, intravenous immunoglobulin, rituximab, and plasmapheresis) were also recorded.
Patients were divided into 2 groups for the assessment of present lupus manifestations, laboratory, and treatment: patients with pancreatitis (evaluated at diagnosis of first episode) and patients without pancreatitis (evaluated at the last visit).
Results were presented as an absolute number (frequency) for categorical variables and median (range) or mean ± SD for continuous variables. Categorical variables comparisons were assessed by Pearson χ2 test or Fisher exact test as required. Continuous variables from patients with cSLE with and without pancreatitis were compared by Mann-Whitney test or t test as required. The significance levels of the independent variable were set at 5% (P < 0.05). Holm-Bonferroni correction for multiple comparisons was performed adjusting the significance level.
Pancreatitis was diagnosed in 22 of 852 (2.6%) patients with cSLE. It was classified as 20 (91%) AP, 2 (9%) acute recurrent pancreatitis, and none of them had chronic pancreatitis. Severe pancreatitis was observed in 11 of 22 (50%) patients. None of them had gallstones, traumatic pancreatitis, or reported alcohol and/or tobacco use. Two patients had acute recurrent pancreatitis with 2 distinct episodes, with pain-free interval between the 2 episodes of 1 and 4 years, respectively.
The first pancreatitis episode was observed at disease onset in 6 (27%) patients with cSLE. Clinical manifestations, laboratory examinations, imaging, and treatment in 22 patients with cSLE according to the first episode of pancreatitis were included as shown in Table 1. The main clinical features of the first episode of pancreatitis were abdominal pain in 20 and vomiting in 20. Serum amylase was increased in all patients and lipase in 20 (7 of them had ≥ 7-fold than the upper limit of normal). Imaging evaluation was carried out in 16 of 22 (73%) patients. Abdominal ultrasound was performed in 12 patients with cSLE with pancreatitis and revealed pancreatic edema in 5 of 12, all of them had elevated amylase and lipase. Abdominal CT was carried out in 12 cSLE and solely pancreatic edema was evidenced in 6 of 12, pancreatic necrosis in 1 of 12, and pancreatic edema with peripancreatic fluid collections and adjacent gas bubbles in 1 of 12. Elevated amylase and lipase levels were observed in 7 of 8 patients with cSLE with abnormal CT. Only 1 patient with pancreatic necrosis evidenced in CT had abdominal pain, vomiting, elevated amylase levels, and without lipase increase (Table 1).
Regarding the outcome, none of them required laparotomy or surgery. Intensive care unit admission was necessary in 21 patients with cSLE owing to severe pancreatitis and active multisystem disease (nephritis in 15/20 [75%] cSLE, serositis in 10/21 [48%], macrophage activation syndrome 8/21 [38%], and neuropsychiatric involvement 2/21 [9%)]). Intravenous fluid was performed in all patients, pain management (morphine or opioids) in 19, and enteral or parenteral nutrition in 20. Seven patients with AP died and 3 of them had serum lipase ≥ 7-fold than the normal limit. At the time of pancreatitis diagnosis, 19 patients were on multiple simultaneous cSLE treatments (Table 1). cSLE patients with AP were treated with intravenous immunoglobulin in 7 and intravenous cyclophosphamide in 8. Fifteen patients were treated with intravenous methylprednisolone and 11 (73%) of them survived. Seven patients died and the causes of death were sepsis in 6 and AKI in 1.
Further comparison of demographic data, clinical manifestations, and disease activity/damage scores in 852 cSLE patients with pancreatitis (first episode) and without pancreatitis are shown in Table 2. After Holm-Bonferroni correction for multiple comparisons (P < 0.0016), disease duration was significantly shorter in patients with pancreatitis compared with those without AP (1 [0–10] vs 4 [0–23] years, P < 0.0001). The frequencies of fever (70% vs 6%, P < 0.0001), weight loss (50% vs 3%, P < 0.0001), hepatomegaly (36% vs 2%, P < 0.0001), splenomegaly (18% vs 1%, P < 0.0001), serositis (45% vs 2%, P < 0.0001), nephritis (75% vs 20%, P < 0.0001), macrophage activation syndrome (36% vs 0.5%, P < 0.0001), arterial hypertension (59% vs 12%, P < 0.0001), acute renal failure (38% vs 3%, P < 0.0001), and death (32% vs 7%, P = 0.001) were significantly higher in patients with cSLE with pancreatitis compared with those without pancreatitis. The median of the present SLE Disease Activity Index 2000 (21 [0–41] vs 2 [0–45], P < 0.0001) was significantly higher in patients with pancreatitis (Table 2).
Laboratory examinations and drug therapy of 852 patients with cSLE according to the first episode of pancreatitis are illustrated in Table 3. After Holm-Bonferroni correction for multiple comparisons (P < 0.0016), erythrocyte sedimentation rate (50 [7–120] vs 19 [1–135] mm/1st hour, P < 0.0001) and C-reactive protein (6.3 [0–486] vs 0.7 [0–404] mg/dL, P < 0.0001) were significantly higher in patients with pancreatitis. The frequencies of leucopenia (48% vs 8%, P < 0.0001), lymphopenia (62% vs 17%, P < 0.0001), thrombocytopenia (62% vs 4%, P < 0.0001), and anti–double-stranded-DNA autoantibodies (82% vs 36%, P < 0.0001) were also significantly higher in patients with pancreatitis. Frequencies of the following treatments were significantly higher in patients with pancreatitis compared with the ones without pancreatitis: intravenous methylprednisolone (68% vs 9%, P < 0.0001), intravenous cyclophosphamide (36% vs 5%, P < 0.0001), and intravenous immunoglobulin (32% vs 2%, P < 0.0001). The median present prednisone dose in mg/day (55 [15–60] vs 11 [1–90] mg/day, P < 0.0001) and the median present prednisone dose in mg · kg−1 · day−1 (1.0 [0.2–2.0] vs 0.2 [0.02–10] mg · kg−1 · day−1, P < 0.0001) were significantly higher in patients with cSLE with pancreatitis. No differences were observed of prednisone cumulative dose, intravenous methylprednisolone cumulative dose, and total glucocorticoid dose in both groups (P > 0.05, Table 3).
Further analysis of the subgroup of 22 cSLE patients with pancreatiits and 66 patients without pancreatitis (randomly selected out of 830 patients with cSLE) that presented similar disease duration (1 [0–10] vs 1 [0–10] years, P = 0.434) and after Holm-Bonferroni correction for multiple comparisons (P < 0.0025), the former group presented higher frequencies of serositis (45% vs 8%, P < 0.0001) and nephritis (75% vs 30%, P < 0.0001). A higher median SLE Disease Activity Index 2000 (21 [0–41] vs 6 [0–35], P < 0.0001) and a higher present prednisone dose in mg/day (55 [15–60] vs 20 [3–60] mg/day, P < 0.0001) were also observed in patients with pancreatitis. The frequencies of intravenous methylprednisolone (68% vs 14%, P < 0.0001), immunosuppressive agents (82% vs 42%, P = 0.001), and intravenous immunoglobulin (32% vs 3%, P = 0.001) were significantly higher in patients with cSLE with pancreatitis.
This multicenter study demonstrates that pancreatitis in cSLE is predominantly an acute and self-limited complication with rare recurrence or chronicity. The advantage of the present study was the inclusion of a large population suffering from a rare autoimmune disease in 10 selected centers of university hospitals, using a standardized protocol to minimize bias. Moreover, classification based on the consensus statement of INSPPIRE allowed a more precise definition of pancreatitis subtypes (11). The main limitation of this study is the retrospective design and possible missing data.
We have confirmed in a large cSLE population that pancreatitis is a rare manifestation of this disease, with a frequency similar to the ones reported in previous case series (6,8,9). More important, the exclusion of major factors related to pancreatitis, including alcohol, tobacco use, and presence of gallstones (3,11), reinforces the possibility that the pancreas is in fact a lupus target organ. The mechanisms suggested for lupus-associated pancreatitis include vasculitis, immune complex deposition, microthrombi, and vascular intimal thickening and ischemia (3,8).
In addition, the high median disease activity score, high frequency of active nephritis, macrophage activation syndrome, and serositis observed in these patients support the notion that pancreatitis occurs in the setting of a global multisystemic inflammation. Severe renal involvement was also reported in patients with cSLE with pancreatitis (10,25).
Pancreatitis has been described early in the course of cSLE, most frequently in the first 2 years of lupus diagnosis (5,6,8), and may be observed at the first manifestation of disease (8), as occurred in one-third of our patients.
We observed herein that cSLE pancreatitis is often severe and occurs in the context of active multisystem disease requiring intensive care unit admission, with a significant high mortality rate. The frequency of cSLE mortality in patients with pancreatitis was 32% and similar to the other groups (25%–54%) (3,9). Overall mortality was high and not attributed to pancreatitis complications in our patients with cSLE, because the majority of deceased patients had sepsis, as also reported in other severe lupus populations (26,27).
Interestingly, 42% of the patients with cSLE with high serum lipase levels (7X) deceased. Indeed, one paper had suggested that this examination could be a predictor of severity of pediatric pancreatitis, with high sensitivity and negative predictive value (28). Other data, however, suggest this is not a reliable measure (29).
In addition, AKI may be a cause of elevated serum lipase (30). The concomitant high levels of lipase and amylase and clinical symptoms of pancreatitis in our patients with cSLE with AKI indicated that uremia was not the major cause of lipase elevation.
Imaging is not necessary for pancreatitis diagnosis, if the other 2 criteria are present. Abdominal ultrasound is frequently normal in patients with pancreatitis and more commonly used instead of CT in pediatric populations, owing to the low risk of radiation exposure (11). CT and magnetic resonance images are accurate examinations for pancreatitis diagnosis and may also provide useful information to predict severe outcome, including pancreatic edema, necrosis, peripancreatic fluid collections, and adjacent gas bubbles (31), as observed in our patients. Imaging evaluation was not assessed in 6 patients because of the unavailability and all had pancreatitis diagnosis confirmed by clinical and laboratory parameters.
The use of high present doses of glucocorticoid seems to indicate a marker of disease severity herein. The finding that 73% of the patients treated with intravenous methylprednisolone therapy survived suggests that this drug may, in fact, contribute to the favorable prognosis, as earlier reported in patients with cSLE and adult-SLE (3,5,7,8). In addition, early management of pancreatitis included intravenous fluid, pain managements, nutritional support, intravenous immunoglobulin, and immunosuppressive therapy (11,15).
In conclusion, this was the first study phenotyping pancreatitis according to the INSPPIRE-standardized definitions in cSLE, revealing a clear predominance of acute subtype and an association with disease activity, severity, and present glucocorticoid use.
Our gratitude to Ulysses Doria-Filho for the statistical analysis. The authors thank the following Pediatric Rheumatology Divisions and colleagues for including their patients: Pediatric Rheumatology Unit, FMUSP (Adriana Maluf Elias Sallum, Cristina Miuki Abe Jacob, Gabriela Blay, Gabriela Nunes Leal, Gabriella Erlacher Lube de Almeida, Heloisa Helena de Souza Marques, João Domingos Montoni da Silva, Joaquim Carlos Rodrigues, Juliana Caíres de Oliveira Achili Ferreira, Kátia Kozu, Laila Pinto Coelho, Luciana dos Santos Henriques, Magda Carneiro-Sampaio, Mariana Ferriani, Marco Felipe Castro Silva, Maria Helena Vaisbich, Lucia Maria Arruda Campos, Roberta Cunha Gomes, Werther Brunow de Carvalho); Pediatric Rheumatology Unit, UNIFESP (Ana Paula Sakamoto, Anandreia Simões Lopes, Claudio Arnaldo Len, Daniela Petry Piotto, Giampaolo Faquin, Gleice Clemente, Maria Odete Esteves Hilário, Melissa Fraga, Octavio Augusto Bedin Peracchi, Vanessa Bugni); Division of Rheumatology, FMUSP (Juliane A Paupitz, Glauce Leão Lima); UNESP (Priscila R. Aoki, Juliana de Oliveira Sato, Silvana Paula Cardin, Taciana Albuquerque Pedrosa Fernandes), Irmandade da Santa Casa de Misericórdia de São Paulo (Andressa Guariento, Eunice Okuda, Maria Carolina dos Santos, Natali Weniger Spelling Gormenzano, Silvana Brasília Sacchetti), State University of Campinas (Marisa Centeville, Renata Barbosa, Roberto Marini), Ribeirão Preto Medical School—University of São Paulo (Francisco Hugo Gomes, Gecilmara Salviatto Pileggi, Luciana Martins de Carvalho, Paola Pontes Pinheiro), Hospital Infantil Darcy Vargas (Jonatas Libório, Luciana Tudech Pedro Paulo) and Hospital Municipal Infantil Menino Jesus (Tânia Caroline Monteiro de Castro).
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