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Prognostic Impact of Atypical Presentation in Pediatric Systemic Lupus Erythematosus: Results from a Multicenter Study
Prognostic Impact of Atypical Presentation in Pediatric Systemic Lupus Erythematosus: Results from a Multicenter Study Andrea Taddio, MD, Elena Rossetto, MD, Carlos D. Rose´, MD, Anne M. Brescia, MD, Claudia Bracaglia, MD, Elisabetta Cortis, MD, Donato Rigante, MD, Achille Stabile, MD, Marcella Montico, MD, Luca Ronfani, MD, Alessandro Ventura, MD, and Loredana Lepore, MD Objectives The aim of the study is to assess the rate of atypical manifestations at onset in pediatric systemic lupus erythematosus (SLE) and to evaluate their effect on disease outcome. Study design This is a multicenter retrospective cohort study. A manifestation was considered atypical if it was not included in the American College Rheumatology classification criteria for SLE but was reported in literature as associated with SLE. Unfavorable outcome was considered presence of organ damage in the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index at the last available evaluation. Results One hundred patients were enrolled in the study; 24% presented atypical clinical features at onset. Univariate analysis showed a significant association of worse outcome variables with the presence of atypical manifestations at onset (P = .004), as well as renal involvement (P = .027). A multivariate logistic regression analysis showed that atypical manifestations at onset (P = .018), renal involvement at onset or during follow up (P = .024), and central nervous system disease involvement during follow up (P = .021) were independent predictors of poor prognosis. Conclusions Our data support a relatively high rate of atypical onset in pediatric SLE. Presence of atypical manifestations at presentation and early kidney disease correlate with poor outcome. Similarly, during follow-up, kidney and central nervous system diseases are associated with worse outcome. (J Pediatr 2010;156:972-7).
S
ystemic lupus erythematosus (SLE) is a multisystem, inflammatory, autoimmune disease that affects both children and adults, with approximately 20% of cases starting in childhood. The course of SLE is characterized by periods of flare and remission, and inflammation can result in irreversible tissue damage, as well as premature death.1 Despite numerous reports of SLE in adults,2 in the recent years there have been few reports on the clinical and laboratory features of pediatric SLE at presentation.3 Although adult and pediatric SLE share clinical features, it has been suggested that children have a more severe and aggressive disease course4 and may present different signs and symptoms at onset: in fact about one third of patients with pSLE may have nonclassical manifestations at presentation that may be responsible for major diagnostic delay in this age group.5 A few studies report the prognostic impact of the clinical pattern of presentation in children with pSLE. Ravelli et al6 found that outcome was significantly impaired in patients with pSLE who had experienced neuropsychiatric manifestations at diagnosis, as well as those who had longer disease duration and had received more intravenous pulses of cyclophosphamide; disease severity according to the age at presentation has also been reported as predictive of poor functional outcome.7-9 Considering the high incidence of atypical manifestations in pSLE and the fact that the impact of nonclassical presentation has never been systematically studied in relation to disease outcome, we conducted a retrospective multicenter study to describe the clinical characteristics of a population with pSLE at onset; in particular we evaluated the rate of atypical clinical manifestations at onset and during the follow-up and their relationship to disease outcome.
Methods Study design and patients selection This is a multicenter retrospective cohort study; it was based on Institutional Review Board (IRB)–approved record review. The records of patients who met the
ACR pSLE SLE SLICC-SDI
American College of Rheumatology Pediatric systemic lupus erythematosus Systemic lupus erythematosus Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index
From the Department of Sciences of Reproduction and Development, Institute of Child Health IRCCS Burlo Garofolo, University of Trieste, Trieste, Italy (A.T., E.R., A.V., L.L.); and the Epidemiology and Biostatistics Unit, Institute of Child Health, IRCCS Burlo Garofolo, Trieste, Italy (M.M., L.R.); the Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesu`, Rome, Itlay (C.B., E.C.); the Department of Pediatric Sciences, Universita` Cattolica Sacro Cuore (D.R., A.S.), Rome, Italy; and the Division of Rheumatology A.I. duPont Hospital for Children, Department of Pediatrics, Thomas Jefferson University, Wilmington, DE (C.R., A.B.) The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.12.022
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Vol. 156, No. 6 June 2010 modified 1997 American College of Rheumatology (ACR) classification criteria for SLE10,11 and had disease onset before 18 years were reviewed. Fulfillment of 4 classification criteria of the ACR at the time of diagnosis was not mandatory but was required to be present within 1 year from diagnosis. All patients were first seen between 1990 and 2005 in the following 4 tertiary care centers: (1) Department of Pediatrics, IRCCS Burlo Garofolo, University of Trieste, Italy; (2) Division of Rheumatology A.I. duPont Hospital for Children, Department of Pediatrics, Wilmington, Delaware; (3) Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesu`, Rome, Italy; and (4) Department of Pediatric Sciences, Universita` Cattolica Sacro Cuore, Rome, Italy. Data collection Patients were divided into 2 groups on the basis of the presence or absence at onset of at least 1 atypical clinical manifestation attributable to SLE. To consider the atypical clinical manifestations at onset and during follow-up, a systematic literature search on PubMed and Embase was performed: any organ involvement reported in the literature but not included in the ACR classification criteria was considered atypical. The following atypical clinical features were observed: gastrointestinal involvement (abdominal pain, acute abdomen, intestinal perforation, intestinal bleeding, hemorrhagic or aseptic peritonitis, pseudoobstruction, pancreatitis, hepatitis, and cholecystitis)5,12-19; cardiac involvement (myocarditis, acute valvular insufficiency)20,21; ocular involvement (retinal vasculitis, posterior uveitis)22; pulmonary involvement (acute and chronic lupus pneumonitis, pulmonary hemorrhage)23,24; endocrinopathy (hypoparathyroidism, primary hyperparathyroidism, hypothyroidism, parotitis, sicca syndrome)5,25,26; neurologic involvement (chorea)5; and hemolytic-uremic syndrome.27 The following parameters were also recorded for each patient at the time of diagnosis: age, sex, ethnicity, family history for autoimmune conditions in first- and second-degree relatives, disease duration at diagnosis, and clinical and laboratory characteristics at diagnosis. The initial presentation of the disease included clinical findings recorded up to the first month after diagnosis. The first laboratory and imaging testing results available at presentation were recorded, including complete blood cell count, hemoglobin, erythrocyte sedimentation rate, C-reactive protein, liver function test (alanine aminotransferase and aspartate aminotransferase), coagulation assessment, urinalysis, complement level (C3, C4), antiphospholipid antibodies, Coombs’ test, antinuclear antibodies, anti-dsDNA, anti Ro-SSA, anti La-SSB, anti-SM, and anti-RNP. Outcome Outcome was measured as cumulative organ damage assessed with the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC-SDI),28 which consists of 41 items in 12 organ system/domains. Damage is defined as any nonreversible change not related to active inflammation occurring after onset of
SLE, ascertained by clinical assessment and present for at least 6 months. The damage index score can only increase over time, theoretically to a maximum of 47. Although not included in classical SDI, we included, as suggested by some authors, growth failure.29 We divided our population into 2 groups: patients with good outcome (absence of organ damage at the end of follow-up) and patients with bad outcome (presence of at least 1 score in the SDI). Statistical analysis All the data have been saved in an Excel database. Statistical analysis was carried out with Stata 9 statistical software (StataCorp, College Station, Texas). Descriptive statistics were used for clinical and laboratory parameters. We realized first a univariate analysis, testing the effects of each collected explanatory variable (independent variables) on the main outcome variable (dependent variable). Pearson c2 testing or Fisher’ s exact test was used to compare categorical and ordinal data, and Student’ s t test was used to analyze continuous data. If continuous data had not a non-normal distribution, a nonparametric test (Mann-Whitney test) was used. Explanatory variables associated with dependent variables at univariate analysis with a P level <.05 were entered in a logistic regression model, to identify variables with strong and independent association with the main outcome variables.
Results The cohort consisted of 100 patients (79 females and 21 males; ratio, 3.8:1), with a mean age at diagnosis of 12.7 3.1 years (range 3 to 18 years). The mean follow-up was 5.3 2.3 years (range 3-10 years). Sixty-eight patients were white, 24 were black, 5 were Hispanic, 2 were Asian, and 1 was Indian. The recruitment of patients divided per center was as follows: 13 patients (12 white and 1 Hispanic) at the Department of Pediatrics, IRCCS Burlo Garofolo, University of Trieste, Italy; 53 patients (24 black; 23 white, 4 Hispanic, 1 Asian, and 1 Indian) at the Division of Rheumatology A.I. duPont Hospital for Children, Department of Pediatrics, Wilmington, Delaware; 21 patients (20 white and 1 Asian) at the Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesu`, Rome, Italy and 13 patients (13 white) at the Department of Pediatric Sciences, Universita` Cattolica Sacro Cuore, Rome, Italy. At least 1 atypical manifestation was present in 24 patients, whereas 76 patients showed only classical manifestations. A family history of autoimmune disease was present in 27 patients (27%) and included mostly SLE present in 10 children, rheumatoid arthritis in 9 patients, and insulin- dependent diabetes mellitus (IDDM) in 3 patients. Other familial autoimmune diseases included hypothyroidism (2 patients), psoriasis (2 patients), Raynaud’ s syndrome (1 patient), and Wegener’ s granulomatosis (1 patient). Among classical clinical manifestations, cutaneous, musculoskeletal, and hematologic symptoms were the most 973
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Table I. Atypical manifestations at onset in a cohort of patients with pSLE No. (%) Gastrointestinal involvement Abdominal pain Acute abdomen Intestinal perforation Intestinal bleeding Hemorrhagic or aseptic peritonitis Pseudoobstruction Pancreatitis Hepatitis Cholecystitis Cardiac involvement Myocarditis Acute valvular insufficiency Ocular involvement Retinal vasculitis Posterior uveitis Pulmonary involvement Acute or chronic lupus pneumonitis Pulmonary hemorrhage Endocrinopathy Hypoparathyroidism Primary hyperparathyroidism Hypothyroidism Parotitis Sicca syndrome Neurologic involvement (Chorea) HUS
26 (67%) 6 7 1 4 — — 1 6 1 3 (8%) 1 2 2 (5%) 2 — 2 (5%) 1 1 6 (15%) — — — 1 5 — —
common. Seventy-two patients presented cutaneous manifestations at onset represented mostly by malar rash (51/ 72), photosensitivity (9/72), small-sized vessel leukocytoclastic vasculitis with intravascular thrombosis in the deep dermis (7/72), and Raynaud’ s phenomenon (6/72). Five of 72 patients experienced livedo reticularis and petechial/purpuric lesions, and 4 patients had alopecia. Sixty-five patients presented musculoskeletal symptoms, mostly arthritis or arthralgia. Abnormal hematologic findings were present in 45 patients and included leukopenia (27/45), autoimmune hemolytic anemia (5/45), and thrombocytopenia (18/45). Fever was also a common clinical feature at onset, being present in 42 patients. Kidney disease was present at onset in 35 patients. It included proteinuria > 0.5 g/d (25/35), casts in urinalysis (10/35), acute kidney failure (4/35), and nephrotic syndrome (7/35). During the disease course, 31 patients underwent kidney biopsy: 9 patients had WHO class V histology, 11 had class IV, 6 had class III, 2 had class II, and 3 could not be classified according to WHO classification. Central nervous system involvement was present in 19 patients and included headache (10/19), seizures (3/19), cerebral vasculitis (3/19), peripheral polyneuropathy (3/19), psychosis (3/19), and mood disorders (3/19). Twenty-four of 100 patients presented at least 1 atypical clinical manifestation at onset; 7 patients presented 2 atypical manifestations, and only 1 child exhibited simultaneously 3 atypical clinical manifestations. The total number of atypical manifestations was 39. Gastrointestinal manifestations were the most common atypical features (26 out of 39 atypical manifestations). In particular, 7 patients presented an acute abdomen, which led to laparotomy, including 3 who 974
Figure. Presenting manifestations and laboratory data at onset of patients with pSLE.
underwent intestinal resection for intestinal vasculitis (2 patients) and vasculitic appendicitis (1 patient). The other 4 patients presented intestinal vasculitis (1 case), pancreatitis (1 case), lupoid hepatitis (1 case), and cholecystitis (1 case). Other gastrointestinal symptoms included intestinal bleeding (4 children) resulting from intestinal vasculitis in 3 patients and inflammatory bowel disease in 1 case; unspecific abdominal pain was recorded in 6 patients, whereas 6 patients presented hepatitis. Other nonclassical involvements included pulmonary, ocular, cardiac, and endocrinopathy symptoms. All the atypical manifestations are presented in Table I. At onset the median value of the erythrocyte sedimentation rate was 76 mm/h (mean 38.6; range 5-145) and the C-reactive protein was 4.3 mg/dL (mean 2.9; range 014.2). Urinalysis was altered in 41% of patients, liver enzymes were increased in 22%, whereas coagulation assessment was impaired (prolongation of aPTT and prothrombin time) in 21%. ANA was positive (>1:80 on HEp 2 cell line) in 96% of children; 90% of patients tested positive for anti-ds DNA antibodies (>30 U.I./mL); antibodies anti-SM were positive in 35% of patients (> 10 U/mL); antibodies antiRo/SSA in 34%; antibodies (>10 U/mL) anti-LA/SSB in 22% (>10 U/mL); and antibodies antiphospholipid (LAC positivity; immunoglobulin M or G anticardiolipin antibodies > 20 U/mL; immunoglobulin M or G anti b2-glycoprotein I > 20 U/mL) in 50%. The Coombs’ test result was positive in 42% of patients. C3 or C4 levels were found under the normal value in 51 out of 78 patients and in 18 of 25 patients, respectively. The median value of C3 was 64 mg/dL (mean 35; range 13-149), whereas the median value of C4 was 9.9 mg/dl (mean 8.2; range 2-65). The overall incidence rate of initial clinical manifestations and laboratory examinations is presented in the Figure. With regard to with the therapeutic option used in patients with SLE included in the study, all of them underwent at least 1 corticosteroid Taddio et al
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Table II. Comparison between clinical manifestations at onset and organ damage at the end of follow-up by univariate analysis (Pearson’s c2) Clinical presentation onset Renal yes no Atypical yes no Cutaneous Yes no Musculoskeletal Yes no Hematologic Yes no Constitutional Yes no Mucosal Yes no Neurologic Yes no Serositis Yes no
Number of patients with organ damage / Total number of patients
P value .027
17/35 17/65 .004 14/24 20/76 NS 26/72 8/27 NS 21/65 13/34 NS 18/45 14/50 NS 14/42 20/57 NS 7/20 27/77 NS 9/19 25/80
a significant association by univariate analysis for the presence at onset of atypical manifestations (14/24 vs 20/76, P = .004) and, among ACR classification criteria, of renal involvement (17/35 vs 17/65, P = .027; Table II). During the follow-up period, renal involvement was confirmed to be significantly associated with worse outcome (21/41 vs 13/56, P = .009), as well as presence of central nervous system disease (17/33 vs 17/67, P = .02). Black ethnicity was also associated with poorer outcome (P = .025). A multivariate logistic regression analysis adjusted for ethnicity (black vs others) and years of follow-up showed the presence of atypical manifestations at onset (P = .018), renal involvement at onset or during follow-up (P = .024), and central nervous system disease during follow-up (P = .021) as independent predictors of poor prognosis. No predictive association was found with laboratory testing at onset except for lower C3 (25/34 vs 2/17, P = .011) and C4 levels (10/18 vs 0/7, P = .011). Moreover, kidney disease at onset was correlated with the presence of hypocomplementemia; here again lower values of C3 were associated with higher prevalence of renal involvement (P = .03). No statistically significant association was found with anti-La/SSB, anti-Ro/SSA, anti-RNP, ANCA, and antiphospholipid antibodies.
NS 6/10 29/89
course, 34 of them underwent at least 1 steroid pulse course (methylprednisolone 30 mg/kg/pulse); 62 patients underwent at least 1 course of hydroxychloroquine, 43 patients of cyclophosphamide, 41 patients of azathioprine, 22 patients of mycophenolate mofetil, 12 patients of intravenous immunoglobulin infusions, and 9 patients of methotrexate; rituximab was tried in 7 patients whereas plasmapheresis was carried out in 3 patients. Finally 2 patients experienced anakinra and infliximab, respectively. Thirty-four patients scored at least 1 on the SLICC-SDI. The most commonly seen complications were ocular (10 patients; 7 with cataract and 3 with retinal change), peripheral vascular (8 patients; 5 with minor tissue loss, 2 with venous thrombosis with swelling, ulceration, or venous stasis, and 1 with significant tissue loss), musculoskeletal (7 patients with avascular necrosis), renal (7 patients; 4 with end-stage renal disease and 3 with $3.5 g/24 hours), and skin involvement (7 patients; 5 with scarring chronic alopecia and 2 with skin ulceration). Less common disease complications were gastrointestinal (4 patients; 3 with infarction per resection of bowel below duodenum and 1 with stricture or upper gastrointestinal tract surgery), neuropsychiatric (3 patients; 2 with cerebrovascular accident and 1 with cognitive impairment), and pulmonary involvement (2 patients; 1 with pulmonary fibrosis and 1 with pleural effusion). Growth retardation was present in 12 patients. The relationship between initial clinical features and outcome variables (presence of organ damage at the end of follow-up) showed
Discussion We found that nonclassical clinical manifestations of the disease are present at onset in one fourth of patients with pSLE. As reported by other authors4 and also in our series, the gastrointestinal manifestations were the atypical symptoms most frequently reported, including 7 children in this cohort who presented with acute abdomen and needed to undergo laparotomy. These findings stress the importance of considering SLE in differential diagnosis of those patients presenting with febrile acute abdomen. Cardiac manifestations associated with fever were the only initial clinical signs attributable to SLE in 3 patients. Both the high prevalence of atypical symptoms at onset and the importance of gastrointestinal manifestations in pSLE have already been reported by others,5,11 but the association with disease outcome was unknown. Studies on early clinical predictors of outcome in pSLE have shown association between young age at the diagnosis,7 male sex,30 nonwhite ethnicity,31 and poor prognosis. Our data do not confirm these findings except for black ethnicity, which was associated with poorer outcome. To date the only clinical features consistently associated with poor prognosis are renal and neurologic involvement,3 which showed prediction for organ damage in our cohort as well. Lupus nephritis both at onset and during follow-up was predictive of organ damage, as were neuropsychiatric manifestations during follow-up. Our data showed that the presence of atypical manifestations is common at presentation and independently predicted poor outcome in patients with pSLE by multivariate analysis. The predictive value for poor outcome could have at least 2
Prognostic Impact of Atypical Presentation in Pediatric Systemic Lupus Erythematosus: Results from a Multicenter Study
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different explanations. On one hand the SLICC-SDI is weighted in favor of gastrointestinal organ damage, a manifestation overrepresented in our set of atypical manifestations. The other possibility is the presence of subjacent vasculitis among the atypical set of manifestations, a condition that carries in itself a higher risk of organ damage and medication use. In support of this matter is the fact that a multivariate regression analysis showed that those patients who presented with atypical features frequently underwent more intravenous steroid pulses (data not shown) and were exposed for longer periods to high-dose steroids (data not shown) than patients who manifested classical clinical features at onset. Interestingly only 7 patients presented with atypical clinical features during the follow-up period, and 5 of them had already experienced nonclassical manifestations at onset. Among theses patients, 5 presented with pulmonary involvement (interstitial lung disease in 2 patients and lupus pneumonia in 3), and lupoid hepatitis and retinal vasculitis were present in 1 patient, respectively. We consider with interest the difference rate of atypical manifestations from onset to follow-up; we could speculate about the presence of 2 different subtypes of patients affected by SLE: the first population presenting with atypical manifestations who have an independent higher risk to accumulate more organ damage during follow-up and those presenting with classical clinical features whose prognosis will be determined from the presence of neurologic or renal involvement. In our cohort 26 of 100 patients did not fulfill the ACR classification criteria at the time of diagnosis, and 9 of 26 presented only with atypical features. Here again gastrointestinal symptoms were the most represented, in fact among this subset of patients 4 of them presented with acute abdomen, in 2 cases they underwent intestinal resection (for vascular appendicitis in 1 child and intestinal vasculitis in another); the other 2 patients underwent laparoscopy and were diagnosed with pancreatitis and intestinal vasculitis. The fifth child presented with lupoid hepatitis; 1 patient presented with intestinal bleeding; in 3 cases cardiac manifestations were the only clinical symptoms: acute mitral insufficiency in 2 patients and myocarditis in the last one. It is important to underline that almost 10% of patients presenting with pSLE may not present any classical clinical sign of SLE. It’ s especially in these cases that laboratory tests (anemia, thrombocytopenia, leucopenia or lymphopenia, or ANA titer) could represent a valid help in reinforcing the diagnostic suspect, as in our cohort. Thirty-four patients scored at least 1 on the SLICC-SDI. No difference was found between the presence of atypical manifestations and specific organ damage except for those patients who presented gastrointestinal manifestations at onset for presence of intestinal resection (P = .037) and avascular necrosis (P = .006) and those who presented ocular involvement for presence of cataract (P = .012). Twelve patients presented growth retardation that, although not included in the standard SLICC-SDI, represents a specific morbidity of the pediatric population and an important disease-related complaint. 976
Vol. 156, No. 6 Another interesting finding is that, among patients with organ damage, the percentage of patients presenting at least 1 SLICC score within the first year of follow-up is greater in the subgroup of patients presenting with atypical manifestations rather than in the subgroup presenting with classical manifestations (64% vs 40%; P = NS). The percentages of patients with ANA, anti-DNA, and antiSM anti-RNP were similar to those in previous studies conducted on patients with pSLE3. The percentage of patients with antiphospholipid antibodies at diagnosis was slightly higher than those reported in other articles, as well as the frequencies of anti-Ro antibodies and anti-La antibodies. However, differently from that reported by others, we didn’ t find any association between platelet count32 and antiphospholipid antibodies33 at onset and outcome, except for lower levels of complement (C3 and C4) that were predictive for renal involvement and consequently for organ damage. In conclusion, this study has confirmed that patients with pSLE have a high incidence of atypical clinical manifestations at onset (24%) and has shown that it significantly correlates with organ damage. Almost 10% of patients may not present any ACR classification criteria at onset leading to a major risk for diagnostic and therapeutic delay. Pediatricians should consider SLE diagnosis in any patient with a fever and with unexplained organ involvement even if ACR classification criteria are not fulfilled. n Submitted for publication Aug 14, 2009; last revision received Oct 27, 2009; accepted Dec 10, 2009.
References 1. Brunner HI, Silverman ED, To T, Bombardier C, Feldman BM. Risk factor for damage in childhood-onset systemic lupus erythematosus. Arthritis Rheum 2002;46:436-44. 2. Bertoli AM, Alarco´n GS, Calvo-Ale´n J, Ferna´ndez M, Vila´ LM, Reveille JD. Systemic lupus erythematosus in a multiethnic US cohort. XXXIII. Clinical features, course, and outcome in patients with late-onset disease. Arthritis Rheum 2006;54:1580-7. 3. Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr 2008;152:550-6. 4. Bader-Meunier B, Armengaud JB, Haddad E, Salomon R, Desche`nes G, Kone´-Paut I, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr 2005;146:64853. 5. Brunner HI, Gladman DD, Iban˜ez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum 2008;58:556-62. 6. Ravelli A, Duarte-Salazar C, Buratti S, Reiff A, Bernstein B, MaldonadoVelazquez MR, et al. Assessment of damage in juvenile-onset systemic lupus erythematosus: a multicenter cohort study. Arthritis Rheum 2003;49:501-7. 7. Pluchinotta FR, Schiavo B, Vittadello F, Martini G, Perilongo G, Zulian F. Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes. Lupus 2007;16:550-5. 8. Descloux S, Durieu I, Cochat P, Vital-Durand D, Ninet J, Fabien N, et al. Influence of age at disease onset in the outcome of paediatric systemic lupus erythematosus. Rheumatology 2009;48:779-84. 9. Miettunen PM, Ortiz-Alvarez O, Petty RE, Cimaz R, Malleson PM, Cabral DA, et al. Gender and ethnic origin have no effect on long-
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22. Ushiyama O, Ushiyama K, Koarada S, Tada Y, Suzuki N, Ohta A, et al. Retinal disease in patients with systemic lupus erythematosus. Ann Rheum Dis 2000;59:705-8. 23. De Jongste JC, Neijens HJ, Duiverman EJ, Bogaard JM, Kerrebijn KF. Respiratory tract disease in systemic lupus erythematosus. Arch Dis Child 1986;61:478-83. 24. Miller RW, Salcedo JR, Fink RJ, Murphy TM, Magilavy DB. Pulmonary hemorrhage in pediatric patients with systemic lupus erythematosus. J Pediatr 1986;108:576-9. 25. Gazarian M, Rm Laxer, Kooh S, Silverman ED. Hypoparathyroidism associated with systemic lupus erythematosus. J Rheumatol 1995;22:2156-8. 26. Benekli M, Savas MC, Erdem Y, Yalc¸in AU, Yasavul U, Turgan C, et al. Primary hyperparathyroidism in a patient with systemic lupus erythematosus-antiphospholipid syndrome. Nephron 1998;79:215-6. 27. Kawasaki Y, Suzuki J, Nozawa R, Suzuki S, Suzuki HA. 12-year-old girl with hemolytic uremic syndrome as initial symptom of systemic lupus erythematosus and a literature review. Am J Nephrol 2002;22:576-80. 28. Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, et al. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum 1997;40:809-13. 29. Bandeira M, Buratti S, Bartoli M, Gasparini C, Breda L, Pistorio A, et al. Relationship between damage accrual, disease flares and cumulative drug therapy in juvenile-onset systemic lupus erythematosus. Lupus 2006;15:515-20. 30. Carreno L, Lopez-Longo FJ, Monteagudo I, Rodrı´guez-Mahou M, Bascones M, Gonza´lez CM, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus 1999;8:287-92. 31. Font J, Cervera R, Espinosa G, Palleras L, Ramos-Casals M, Jimenez S, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis 1998;57:456-9. 32. Ferna´ndez M, Alarco´n GS, Apte M, Andrade RM, Vila´ LM, Reveille JD. LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort: XLIII. The significance of thrombocytopenia as a prognostic factor. Arthritis Rheum 2007;56:614-21. 33. Descloux E, Durieu I, Cochat P, Vital Durand D, Ninet J, Fabien N, et al. Paediatric systemic lupus erythematosus: prognostic impact of antiphospholipid antibodies. Rheumatology 2008;47:183-7.
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S
ystemic lupus erythematosus (SLE) is a multisystem, inflammatory, autoimmune disease that affects both children and adults, with approximately 20% of cases starting in childhood. The course of SLE is characterized by periods of flare and remission, and inflammation can result in irreversible tissue damage, as well as premature death.1 Despite numerous reports of SLE in adults,2 in the recent years there have been few reports on the clinical and laboratory features of pediatric SLE at presentation.3 Although adult and pediatric SLE share clinical features, it has been suggested that children have a more severe and aggressive disease course4 and may present different signs and symptoms at onset: in fact about one third of patients with pSLE may have nonclassical manifestations at presentation that may be responsible for major diagnostic delay in this age group.5 A few studies report the prognostic impact of the clinical pattern of presentation in children with pSLE. Ravelli et al6 found that outcome was significantly impaired in patients with pSLE who had experienced neuropsychiatric manifestations at diagnosis, as well as those who had longer disease duration and had received more intravenous pulses of cyclophosphamide; disease severity according to the age at presentation has also been reported as predictive of poor functional outcome.7-9 Considering the high incidence of atypical manifestations in pSLE and the fact that the impact of nonclassical presentation has never been systematically studied in relation to disease outcome, we conducted a retrospective multicenter study to describe the clinical characteristics of a population with pSLE at onset; in particular we evaluated the rate of atypical clinical manifestations at onset and during the follow-up and their relationship to disease outcome.
Methods Study design and patients selection This is a multicenter retrospective cohort study; it was based on Institutional Review Board (IRB)–approved record review. The records of patients who met the
ACR pSLE SLE SLICC-SDI
American College of Rheumatology Pediatric systemic lupus erythematosus Systemic lupus erythematosus Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index
From the Department of Sciences of Reproduction and Development, Institute of Child Health IRCCS Burlo Garofolo, University of Trieste, Trieste, Italy (A.T., E.R., A.V., L.L.); and the Epidemiology and Biostatistics Unit, Institute of Child Health, IRCCS Burlo Garofolo, Trieste, Italy (M.M., L.R.); the Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesu`, Rome, Itlay (C.B., E.C.); the Department of Pediatric Sciences, Universita` Cattolica Sacro Cuore (D.R., A.S.), Rome, Italy; and the Division of Rheumatology A.I. duPont Hospital for Children, Department of Pediatrics, Thomas Jefferson University, Wilmington, DE (C.R., A.B.) The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.12.022
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Vol. 156, No. 6 June 2010 modified 1997 American College of Rheumatology (ACR) classification criteria for SLE10,11 and had disease onset before 18 years were reviewed. Fulfillment of 4 classification criteria of the ACR at the time of diagnosis was not mandatory but was required to be present within 1 year from diagnosis. All patients were first seen between 1990 and 2005 in the following 4 tertiary care centers: (1) Department of Pediatrics, IRCCS Burlo Garofolo, University of Trieste, Italy; (2) Division of Rheumatology A.I. duPont Hospital for Children, Department of Pediatrics, Wilmington, Delaware; (3) Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesu`, Rome, Italy; and (4) Department of Pediatric Sciences, Universita` Cattolica Sacro Cuore, Rome, Italy. Data collection Patients were divided into 2 groups on the basis of the presence or absence at onset of at least 1 atypical clinical manifestation attributable to SLE. To consider the atypical clinical manifestations at onset and during follow-up, a systematic literature search on PubMed and Embase was performed: any organ involvement reported in the literature but not included in the ACR classification criteria was considered atypical. The following atypical clinical features were observed: gastrointestinal involvement (abdominal pain, acute abdomen, intestinal perforation, intestinal bleeding, hemorrhagic or aseptic peritonitis, pseudoobstruction, pancreatitis, hepatitis, and cholecystitis)5,12-19; cardiac involvement (myocarditis, acute valvular insufficiency)20,21; ocular involvement (retinal vasculitis, posterior uveitis)22; pulmonary involvement (acute and chronic lupus pneumonitis, pulmonary hemorrhage)23,24; endocrinopathy (hypoparathyroidism, primary hyperparathyroidism, hypothyroidism, parotitis, sicca syndrome)5,25,26; neurologic involvement (chorea)5; and hemolytic-uremic syndrome.27 The following parameters were also recorded for each patient at the time of diagnosis: age, sex, ethnicity, family history for autoimmune conditions in first- and second-degree relatives, disease duration at diagnosis, and clinical and laboratory characteristics at diagnosis. The initial presentation of the disease included clinical findings recorded up to the first month after diagnosis. The first laboratory and imaging testing results available at presentation were recorded, including complete blood cell count, hemoglobin, erythrocyte sedimentation rate, C-reactive protein, liver function test (alanine aminotransferase and aspartate aminotransferase), coagulation assessment, urinalysis, complement level (C3, C4), antiphospholipid antibodies, Coombs’ test, antinuclear antibodies, anti-dsDNA, anti Ro-SSA, anti La-SSB, anti-SM, and anti-RNP. Outcome Outcome was measured as cumulative organ damage assessed with the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC-SDI),28 which consists of 41 items in 12 organ system/domains. Damage is defined as any nonreversible change not related to active inflammation occurring after onset of
SLE, ascertained by clinical assessment and present for at least 6 months. The damage index score can only increase over time, theoretically to a maximum of 47. Although not included in classical SDI, we included, as suggested by some authors, growth failure.29 We divided our population into 2 groups: patients with good outcome (absence of organ damage at the end of follow-up) and patients with bad outcome (presence of at least 1 score in the SDI). Statistical analysis All the data have been saved in an Excel database. Statistical analysis was carried out with Stata 9 statistical software (StataCorp, College Station, Texas). Descriptive statistics were used for clinical and laboratory parameters. We realized first a univariate analysis, testing the effects of each collected explanatory variable (independent variables) on the main outcome variable (dependent variable). Pearson c2 testing or Fisher’ s exact test was used to compare categorical and ordinal data, and Student’ s t test was used to analyze continuous data. If continuous data had not a non-normal distribution, a nonparametric test (Mann-Whitney test) was used. Explanatory variables associated with dependent variables at univariate analysis with a P level <.05 were entered in a logistic regression model, to identify variables with strong and independent association with the main outcome variables.
Results The cohort consisted of 100 patients (79 females and 21 males; ratio, 3.8:1), with a mean age at diagnosis of 12.7 3.1 years (range 3 to 18 years). The mean follow-up was 5.3 2.3 years (range 3-10 years). Sixty-eight patients were white, 24 were black, 5 were Hispanic, 2 were Asian, and 1 was Indian. The recruitment of patients divided per center was as follows: 13 patients (12 white and 1 Hispanic) at the Department of Pediatrics, IRCCS Burlo Garofolo, University of Trieste, Italy; 53 patients (24 black; 23 white, 4 Hispanic, 1 Asian, and 1 Indian) at the Division of Rheumatology A.I. duPont Hospital for Children, Department of Pediatrics, Wilmington, Delaware; 21 patients (20 white and 1 Asian) at the Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesu`, Rome, Italy and 13 patients (13 white) at the Department of Pediatric Sciences, Universita` Cattolica Sacro Cuore, Rome, Italy. At least 1 atypical manifestation was present in 24 patients, whereas 76 patients showed only classical manifestations. A family history of autoimmune disease was present in 27 patients (27%) and included mostly SLE present in 10 children, rheumatoid arthritis in 9 patients, and insulin- dependent diabetes mellitus (IDDM) in 3 patients. Other familial autoimmune diseases included hypothyroidism (2 patients), psoriasis (2 patients), Raynaud’ s syndrome (1 patient), and Wegener’ s granulomatosis (1 patient). Among classical clinical manifestations, cutaneous, musculoskeletal, and hematologic symptoms were the most 973
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Table I. Atypical manifestations at onset in a cohort of patients with pSLE No. (%) Gastrointestinal involvement Abdominal pain Acute abdomen Intestinal perforation Intestinal bleeding Hemorrhagic or aseptic peritonitis Pseudoobstruction Pancreatitis Hepatitis Cholecystitis Cardiac involvement Myocarditis Acute valvular insufficiency Ocular involvement Retinal vasculitis Posterior uveitis Pulmonary involvement Acute or chronic lupus pneumonitis Pulmonary hemorrhage Endocrinopathy Hypoparathyroidism Primary hyperparathyroidism Hypothyroidism Parotitis Sicca syndrome Neurologic involvement (Chorea) HUS
26 (67%) 6 7 1 4 — — 1 6 1 3 (8%) 1 2 2 (5%) 2 — 2 (5%) 1 1 6 (15%) — — — 1 5 — —
common. Seventy-two patients presented cutaneous manifestations at onset represented mostly by malar rash (51/ 72), photosensitivity (9/72), small-sized vessel leukocytoclastic vasculitis with intravascular thrombosis in the deep dermis (7/72), and Raynaud’ s phenomenon (6/72). Five of 72 patients experienced livedo reticularis and petechial/purpuric lesions, and 4 patients had alopecia. Sixty-five patients presented musculoskeletal symptoms, mostly arthritis or arthralgia. Abnormal hematologic findings were present in 45 patients and included leukopenia (27/45), autoimmune hemolytic anemia (5/45), and thrombocytopenia (18/45). Fever was also a common clinical feature at onset, being present in 42 patients. Kidney disease was present at onset in 35 patients. It included proteinuria > 0.5 g/d (25/35), casts in urinalysis (10/35), acute kidney failure (4/35), and nephrotic syndrome (7/35). During the disease course, 31 patients underwent kidney biopsy: 9 patients had WHO class V histology, 11 had class IV, 6 had class III, 2 had class II, and 3 could not be classified according to WHO classification. Central nervous system involvement was present in 19 patients and included headache (10/19), seizures (3/19), cerebral vasculitis (3/19), peripheral polyneuropathy (3/19), psychosis (3/19), and mood disorders (3/19). Twenty-four of 100 patients presented at least 1 atypical clinical manifestation at onset; 7 patients presented 2 atypical manifestations, and only 1 child exhibited simultaneously 3 atypical clinical manifestations. The total number of atypical manifestations was 39. Gastrointestinal manifestations were the most common atypical features (26 out of 39 atypical manifestations). In particular, 7 patients presented an acute abdomen, which led to laparotomy, including 3 who 974
Figure. Presenting manifestations and laboratory data at onset of patients with pSLE.
underwent intestinal resection for intestinal vasculitis (2 patients) and vasculitic appendicitis (1 patient). The other 4 patients presented intestinal vasculitis (1 case), pancreatitis (1 case), lupoid hepatitis (1 case), and cholecystitis (1 case). Other gastrointestinal symptoms included intestinal bleeding (4 children) resulting from intestinal vasculitis in 3 patients and inflammatory bowel disease in 1 case; unspecific abdominal pain was recorded in 6 patients, whereas 6 patients presented hepatitis. Other nonclassical involvements included pulmonary, ocular, cardiac, and endocrinopathy symptoms. All the atypical manifestations are presented in Table I. At onset the median value of the erythrocyte sedimentation rate was 76 mm/h (mean 38.6; range 5-145) and the C-reactive protein was 4.3 mg/dL (mean 2.9; range 014.2). Urinalysis was altered in 41% of patients, liver enzymes were increased in 22%, whereas coagulation assessment was impaired (prolongation of aPTT and prothrombin time) in 21%. ANA was positive (>1:80 on HEp 2 cell line) in 96% of children; 90% of patients tested positive for anti-ds DNA antibodies (>30 U.I./mL); antibodies anti-SM were positive in 35% of patients (> 10 U/mL); antibodies antiRo/SSA in 34%; antibodies (>10 U/mL) anti-LA/SSB in 22% (>10 U/mL); and antibodies antiphospholipid (LAC positivity; immunoglobulin M or G anticardiolipin antibodies > 20 U/mL; immunoglobulin M or G anti b2-glycoprotein I > 20 U/mL) in 50%. The Coombs’ test result was positive in 42% of patients. C3 or C4 levels were found under the normal value in 51 out of 78 patients and in 18 of 25 patients, respectively. The median value of C3 was 64 mg/dL (mean 35; range 13-149), whereas the median value of C4 was 9.9 mg/dl (mean 8.2; range 2-65). The overall incidence rate of initial clinical manifestations and laboratory examinations is presented in the Figure. With regard to with the therapeutic option used in patients with SLE included in the study, all of them underwent at least 1 corticosteroid Taddio et al
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Table II. Comparison between clinical manifestations at onset and organ damage at the end of follow-up by univariate analysis (Pearson’s c2) Clinical presentation onset Renal yes no Atypical yes no Cutaneous Yes no Musculoskeletal Yes no Hematologic Yes no Constitutional Yes no Mucosal Yes no Neurologic Yes no Serositis Yes no
Number of patients with organ damage / Total number of patients
P value .027
17/35 17/65 .004 14/24 20/76 NS 26/72 8/27 NS 21/65 13/34 NS 18/45 14/50 NS 14/42 20/57 NS 7/20 27/77 NS 9/19 25/80
a significant association by univariate analysis for the presence at onset of atypical manifestations (14/24 vs 20/76, P = .004) and, among ACR classification criteria, of renal involvement (17/35 vs 17/65, P = .027; Table II). During the follow-up period, renal involvement was confirmed to be significantly associated with worse outcome (21/41 vs 13/56, P = .009), as well as presence of central nervous system disease (17/33 vs 17/67, P = .02). Black ethnicity was also associated with poorer outcome (P = .025). A multivariate logistic regression analysis adjusted for ethnicity (black vs others) and years of follow-up showed the presence of atypical manifestations at onset (P = .018), renal involvement at onset or during follow-up (P = .024), and central nervous system disease during follow-up (P = .021) as independent predictors of poor prognosis. No predictive association was found with laboratory testing at onset except for lower C3 (25/34 vs 2/17, P = .011) and C4 levels (10/18 vs 0/7, P = .011). Moreover, kidney disease at onset was correlated with the presence of hypocomplementemia; here again lower values of C3 were associated with higher prevalence of renal involvement (P = .03). No statistically significant association was found with anti-La/SSB, anti-Ro/SSA, anti-RNP, ANCA, and antiphospholipid antibodies.
NS 6/10 29/89
course, 34 of them underwent at least 1 steroid pulse course (methylprednisolone 30 mg/kg/pulse); 62 patients underwent at least 1 course of hydroxychloroquine, 43 patients of cyclophosphamide, 41 patients of azathioprine, 22 patients of mycophenolate mofetil, 12 patients of intravenous immunoglobulin infusions, and 9 patients of methotrexate; rituximab was tried in 7 patients whereas plasmapheresis was carried out in 3 patients. Finally 2 patients experienced anakinra and infliximab, respectively. Thirty-four patients scored at least 1 on the SLICC-SDI. The most commonly seen complications were ocular (10 patients; 7 with cataract and 3 with retinal change), peripheral vascular (8 patients; 5 with minor tissue loss, 2 with venous thrombosis with swelling, ulceration, or venous stasis, and 1 with significant tissue loss), musculoskeletal (7 patients with avascular necrosis), renal (7 patients; 4 with end-stage renal disease and 3 with $3.5 g/24 hours), and skin involvement (7 patients; 5 with scarring chronic alopecia and 2 with skin ulceration). Less common disease complications were gastrointestinal (4 patients; 3 with infarction per resection of bowel below duodenum and 1 with stricture or upper gastrointestinal tract surgery), neuropsychiatric (3 patients; 2 with cerebrovascular accident and 1 with cognitive impairment), and pulmonary involvement (2 patients; 1 with pulmonary fibrosis and 1 with pleural effusion). Growth retardation was present in 12 patients. The relationship between initial clinical features and outcome variables (presence of organ damage at the end of follow-up) showed
Discussion We found that nonclassical clinical manifestations of the disease are present at onset in one fourth of patients with pSLE. As reported by other authors4 and also in our series, the gastrointestinal manifestations were the atypical symptoms most frequently reported, including 7 children in this cohort who presented with acute abdomen and needed to undergo laparotomy. These findings stress the importance of considering SLE in differential diagnosis of those patients presenting with febrile acute abdomen. Cardiac manifestations associated with fever were the only initial clinical signs attributable to SLE in 3 patients. Both the high prevalence of atypical symptoms at onset and the importance of gastrointestinal manifestations in pSLE have already been reported by others,5,11 but the association with disease outcome was unknown. Studies on early clinical predictors of outcome in pSLE have shown association between young age at the diagnosis,7 male sex,30 nonwhite ethnicity,31 and poor prognosis. Our data do not confirm these findings except for black ethnicity, which was associated with poorer outcome. To date the only clinical features consistently associated with poor prognosis are renal and neurologic involvement,3 which showed prediction for organ damage in our cohort as well. Lupus nephritis both at onset and during follow-up was predictive of organ damage, as were neuropsychiatric manifestations during follow-up. Our data showed that the presence of atypical manifestations is common at presentation and independently predicted poor outcome in patients with pSLE by multivariate analysis. The predictive value for poor outcome could have at least 2
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different explanations. On one hand the SLICC-SDI is weighted in favor of gastrointestinal organ damage, a manifestation overrepresented in our set of atypical manifestations. The other possibility is the presence of subjacent vasculitis among the atypical set of manifestations, a condition that carries in itself a higher risk of organ damage and medication use. In support of this matter is the fact that a multivariate regression analysis showed that those patients who presented with atypical features frequently underwent more intravenous steroid pulses (data not shown) and were exposed for longer periods to high-dose steroids (data not shown) than patients who manifested classical clinical features at onset. Interestingly only 7 patients presented with atypical clinical features during the follow-up period, and 5 of them had already experienced nonclassical manifestations at onset. Among theses patients, 5 presented with pulmonary involvement (interstitial lung disease in 2 patients and lupus pneumonia in 3), and lupoid hepatitis and retinal vasculitis were present in 1 patient, respectively. We consider with interest the difference rate of atypical manifestations from onset to follow-up; we could speculate about the presence of 2 different subtypes of patients affected by SLE: the first population presenting with atypical manifestations who have an independent higher risk to accumulate more organ damage during follow-up and those presenting with classical clinical features whose prognosis will be determined from the presence of neurologic or renal involvement. In our cohort 26 of 100 patients did not fulfill the ACR classification criteria at the time of diagnosis, and 9 of 26 presented only with atypical features. Here again gastrointestinal symptoms were the most represented, in fact among this subset of patients 4 of them presented with acute abdomen, in 2 cases they underwent intestinal resection (for vascular appendicitis in 1 child and intestinal vasculitis in another); the other 2 patients underwent laparoscopy and were diagnosed with pancreatitis and intestinal vasculitis. The fifth child presented with lupoid hepatitis; 1 patient presented with intestinal bleeding; in 3 cases cardiac manifestations were the only clinical symptoms: acute mitral insufficiency in 2 patients and myocarditis in the last one. It is important to underline that almost 10% of patients presenting with pSLE may not present any classical clinical sign of SLE. It’ s especially in these cases that laboratory tests (anemia, thrombocytopenia, leucopenia or lymphopenia, or ANA titer) could represent a valid help in reinforcing the diagnostic suspect, as in our cohort. Thirty-four patients scored at least 1 on the SLICC-SDI. No difference was found between the presence of atypical manifestations and specific organ damage except for those patients who presented gastrointestinal manifestations at onset for presence of intestinal resection (P = .037) and avascular necrosis (P = .006) and those who presented ocular involvement for presence of cataract (P = .012). Twelve patients presented growth retardation that, although not included in the standard SLICC-SDI, represents a specific morbidity of the pediatric population and an important disease-related complaint. 976
Vol. 156, No. 6 Another interesting finding is that, among patients with organ damage, the percentage of patients presenting at least 1 SLICC score within the first year of follow-up is greater in the subgroup of patients presenting with atypical manifestations rather than in the subgroup presenting with classical manifestations (64% vs 40%; P = NS). The percentages of patients with ANA, anti-DNA, and antiSM anti-RNP were similar to those in previous studies conducted on patients with pSLE3. The percentage of patients with antiphospholipid antibodies at diagnosis was slightly higher than those reported in other articles, as well as the frequencies of anti-Ro antibodies and anti-La antibodies. However, differently from that reported by others, we didn’ t find any association between platelet count32 and antiphospholipid antibodies33 at onset and outcome, except for lower levels of complement (C3 and C4) that were predictive for renal involvement and consequently for organ damage. In conclusion, this study has confirmed that patients with pSLE have a high incidence of atypical clinical manifestations at onset (24%) and has shown that it significantly correlates with organ damage. Almost 10% of patients may not present any ACR classification criteria at onset leading to a major risk for diagnostic and therapeutic delay. Pediatricians should consider SLE diagnosis in any patient with a fever and with unexplained organ involvement even if ACR classification criteria are not fulfilled. n Submitted for publication Aug 14, 2009; last revision received Oct 27, 2009; accepted Dec 10, 2009.
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