Autoimmunity Reviews 13 (2014) 157–162
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Review
Pediatric catastrophic antiphospholipid syndrome: Descriptive analysis of 45 patients from the “CAPS Registry” Horacio Berman a,1, Ignasi Rodríguez-Pintó a,1, Ricard Cervera a, Simone Gregory b, Ernesto de Meis b, Carlos Ewerton Maia Rodrigues c, Nádia Emi Aikawa c,d, Jozélio Freire de Carvalho c, Janusz Springer e, Maciej Niedzwiecki e, Gerard Espinosa a,⁎, on behalf of the Catastrophic Registry Project Group (European Forum on Antiphospholipid Antibodies) 2 a
Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Catalonia, Spain Department of Hematology, National Cancer Institute, Rio de Janeiro, Brazil c Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil d Pediatric Rheumatology Unit, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil e Medical University of Gdansk, Poland b
a r t i c l e
i n f o
Article history: Received 1 October 2013 Accepted 13 October 2013 Available online 19 October 2013 Keywords: Catastrophic antiphospholipid syndrome Antiphospholipid syndrome Pediatric Infant
a b s t r a c t Given the lack of information about catastrophic antiphospholipid syndrome (APS) in pediatric patients, the objective of the current study was to describe the clinical characteristics, laboratory features, treatment, and outcome of pediatric patients with catastrophic APS and compare them with the adult patients with catastrophic APS. We identified patients who were under 18 years of age at time of catastrophic APS diagnosis included in the international registry of patients with catastrophic APS (CAPS Registry). Their main demographic and clinical characteristics, laboratory features, treatment, and outcome were described and compared with those of adult patients with catastrophic APS. From the 446 patients included in the CAPS Registry as of May 2013, 45 (10.3%) patients developed 46 catastrophic events before 18 years of age (one patient presented two episodes). Overall, 32 (71.1%) patients were female and the mean age was 11.5 ± 4.6 years (range, 3 months–18 years). A total of 31 (68.9%) patients suffered from primary APS and 13 (28.9%) from systemic lupus erythematosus (SLE). The main differences between the two groups of patients were the higher prevalence of infections as precipitating factor for catastrophic event in the pediatric population (60.9% versus 26.8% in the adult population, p b 0.001) and of peripheral vessel thrombosis (52.2% versus 34.3%, p = 0.017). In addition, catastrophic APS was the first manifestation of APS more frequently in pediatric patients (86.6% versus 45.2%, p b 0.001). Interestingly, pediatric patients showed a trend of lower mortality, although the difference was not statistically significant (26.1% versus 40.2%; odds ratio, 1.9; 95% confidence interval, 0.96–3.79; p = 0.063). No differences were found neither in the laboratory features nor in the isolated or combination treatments between groups. Catastrophic APS in pediatric patients is a rare disease. There are minimal differences in the clinical and laboratory features, treatment, and outcome of pediatric and adult catastrophic APS patients. © 2013 Elsevier B.V. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . 2.1. Data collection . . . . . . . . . . . . . . 2.2. Statistical analysis . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . 3.1. General characteristics . . . . . . . . . . . 3.2. Precipitating factors and clinical presentation
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⁎ Corresponding author at: Servei de Malalties Autoimmunes, Hospital Clínic, Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail address: [email protected] (G. Espinosa). 1 These two authors contributed equally to this study. 2 See complete list of members at the appendix at the end of article. 1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2013.10.004
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3.3. APS-related laboratory findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Treatment and outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Comparison between pediatric and adult patients with catastrophic APS . . . . . . . . . . . . . . . . . . . . . . 3.6. Comparison between pediatric patients with classic and catastrophic APS . . . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix. The Catastrophic Antiphospholipid Syndrome Registry Project Group (European Forum on Antiphospholipid Antibodies) References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The catastrophic antiphospholipid syndrome (APS) is characterized by multi-organ thrombosis developing over a short period of time [1]. This life-threatening variant of the APS that represents less than 1% of all patients with APS, was first described more than 20 years ago [2]. Since then, more than 400 cases have been collected in the catastrophic APS international registry (CAPS Registry). This registry was created by the European Forum on Antiphospholipid Antibodies, a study group devoted to the development of multi-center projects with large populations of APS patients [3]. The analysis of this registry has generated a cluster of knowledge of the main clinical, and laboratory features as well as the outcome of patients with catastrophic APS [4]. In addition, classification criteria and treatment guidelines for its management have been established [1,5,6]. Age at onset might modulate the clinical expression and prognosis of patients with different autoimmune diseases [7]. Particularly for classic APS, a review of 121 patients with pediatric APS, defined as the onset of APS before the patient's 18th birthday, demonstrated some important differences between the pediatric and adult APS patients [8]. In fact, the high female preponderance in adult patients (female/male ratio of 5:1) with classic APS does not occur in the pediatric subset (1.2:1). Deep venous thrombosis in the legs was the most frequent venous thrombotic event both in pediatric and adult APS patients (40% versus 32%, respectively). However, cerebral sinus venous thrombosis and ischemic stroke as a first manifestation of APS were significantly more frequent in the pediatric APS patients. In addition, the presence of lupus anticoagulant (LAC) was also more frequent in patients with pediatric APS [8]. In the present article, we describe the clinical characteristics, laboratory features, and outcomes of patients who presented with catastrophic APS in the pediatric age and compared them with those of adult patients with catastrophic APS.
2. Patients and methods 2.1. Data collection We identified the patients with catastrophic APS in the pediatric age included in the CAPS Registry, the website-based international registry of patients with catastrophic APS. The sources of information for the CAPS Registry are: a) periodic Medline search of published catastrophic APS reports; and b) personal communication with physicians in charge of catastrophic APS patients for the unpublished cases (physicians fill out a standardized data form collecting demographic, clinical, therapeutic, and outcome information) [3]. The registry documents the clinical, laboratory and therapeutic data of all reported cases of catastrophic APS which can be freely consulted through the website (http://infmed.fcrb.es/en/web/caps). Patients were considered as having pediatric catastrophic APS if the onset of catastrophic episode occurred before 18 years of age. Data from these patients were summarized in a standardized data-form, including sex, age and diagnosis of the underlying disease, precipitating factors,
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main thrombotic clinical features, laboratory findings, treatment, disease evolution and final outcome.
2.2. Statistical analysis Results from continuous variables are presented as mean ± standard deviation (SD) and categorical data as percentages. Comparisons were performed using the Mann–Whitney test for continuous variables, whereas Fisher's exact test was used for categorical variables. Differences were considered significant when p b 0.05.
3. Results 3.1. General characteristics From the 446 patients included in the CAPS Registry since May 2013, 45 (10.3%) patients developed 46 catastrophic events before 18 years of age (one patient presented two episodes). Overall, 32 (71.1%) patients were female and the mean age was 11.5 ± 4.6 years (range, 3 months–18 years) (Table 1). A total of 31 (68.9%) patients suffered from primary APS, 13 (28.9%) from systemic lupus erythematosus (SLE) and one from a lupus-like disease (2.2%).
3.2. Precipitating factors and clinical presentation Precipitating factors were identified in 35 (76.1%) events. Infection was the most frequent precipitating factor found in 28 (60.9%) of them, followed by neoplasia (8; 17.4%), surgery (3; 6.5%), and SLE flares (2; 4.3%), whereas oral contraceptives and Cesarean section accounted for once case each (2.2%). In the remaining case, the precipitating factor was not specified. In nine events, two concomitant precipitating factors were identified. The catastrophic event appeared as the first manifestation of APS in 86.7% of cases. The clinical characteristics of patients with pediatric catastrophic APS are summarized in Table 1. Kidney manifestations were present in 29 (63.0%) episodes and mainly consisted of renal failure, arterial hypertension, and proteinuria. Lung involvement appeared in 29 (63.0%) cases in the form of acute respiratory distress syndrome and pulmonary embolism. Cardiac involvement was present in 27 (57.4%) episodes and included cardiac failure, myocardial infarction and heart valve lesions. Cerebral involvement was also frequent, present in 22 (47.8%) cases, and included encephalopathy, cerebrovascular accidents and seizures. Liver involvement and peripheral venous thrombosis appeared in 19 (40.4%) cases each. The skin was involved in 17 (37.0%) episodes presenting as livedo reticularis, skin ulcers, cutaneous necrosis, gangrene, digital ischemia and purpura. Raynaud's phenomenon was not reported. The gastrointestinal tract was involved in 8 (17.4%) episodes, spleen infarcts were described in 7 (15.2%) and adrenal gland involvement was reported in 3 cases (6.5%). Involvement of bone marrow, peripheral nervous system, pancreas, and eye occurred in less than 5% of patients.
H. Berman et al. / Autoimmunity Reviews 13 (2014) 157–162 Table 1 Demographic features and clinical manifestations of 46 episodes from 45 patients with pediatric catastrophic APS.
Table 2 Comparison of demographic and clinical characteristics, precipitating factors, treatment and mortality between pediatric and adult patients with catastrophic APS.
N (%) Demographics Sex (female/male) Age at the time of pediatric catastrophic APS (years)
32/13 (71/29) 11.5 ± 4.6
Diagnosis Primary APS Systemic lupus erythematosus Systemic lupus erythematosus-like Catastrophic APS as the first manifestation of APS
32 (69.6) 13 (28.3) 1 (2.2) 39 (86.7)
Clinical manifestations Kidney involvement Renal failure Arterial hypertension Proteinuria Lung involvement Acute respiratory distress syndrome Pulmonary embolism Alveolar hemorrhage Heart involvement Heart failure Heart valve disease Myocardial infarction Peripheral vessel thrombosis Venous Arterial Brain involvement Encephalopathy Cerebrovascular accident Seizures Liver involvement Hepatitis Liver failure Skin involvement Livedo reticularis Ulcers Skin necrosis Digital ischemia Purpura Gastrointestinal tract involvement Spleen involvement Adrenal gland involvement
29 (63.0) 22 (47.8) 11 (23.9) 6 (13.3) 29 (63.0) 13 (28.3) 6 (13.0) 2 (4.3) 27 (58.7) 18 (39.1) 2 (4.3) 2 (4.3) 24 (52.2) 19 (41.3) 11 (23.9) 22 (47.8) 10 (21.7) 6 (13.0) 5 (10.9) 19 (41.3) 11 (23.9) 2 (4.3) 17 (37.0) 9 (19.6) 5 (10.9) 5 (10.9) 5 (10.9) 3 (6.5) 8 (17.4) 7 (15.2) 3 (6.5)
Age at the time of catastrophic APS is expressed as mean ± standard deviation. Abbreviations: APS, antiphospholipid syndrome.
3.3. APS-related laboratory findings Thrombocytopenia (≤100,000/mm3) was found in 31/44 (70.5%) cases of pediatric catastrophic APS. The LAC was reported as positive in 78.6% of patients, followed by the IgG isotype of anticardiolipin antibodies (aCL) in 72.5% and the IgM isotype of aCL in 45.7% of them. The IgG isotype of anti-β2-glycoprotein I antibodies was positive in 5/6 patients (83.3%) and the IgM isotype in 3/5 (60.0%) patients. Antinuclear and anti-DNA antibodies were positive in 15/31 (48.4%) and in 13/30 (43.3%) cases, respectively. Six (13.0%) events presented with schistocytes. Unfortunately, no data of disseminated intravascular coagulation were specified. 3.4. Treatment and outcome Anticoagulants (ACs) were the most frequent treatment used in 35 of the 45 (77.8%) cases of pediatric catastrophic APS, followed by corticosteroids (CS) in 34 (75.6%), plasma exchange (PE) in 18 (40.0%), intravenous immunoglobulins (IVIG) in 17 (37.8%), cyclophosphamide in 11 (24.4%) and platelet aggregation inhibitors in 3 (7.0%) (Table 2). Most patients received a combination of therapies. ACs + CS was the most common combination (20.9%), followed by ACs + CS + PE and/ or IVIGs (18.6%), and ACs + CS + cyclophosphamide + PE and/or IVIG (11.6%) (Table 3). Data on treatment were not available in one patient.
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Pediatric cases N (%)
Adult cases N (%)
32/13 (71/29) 31/46 (67.4) 13/46 (28.3) 38/46 (86.6)
267/121 (69/31) 0.752 232/400 (59.7) 0.220 119/400 (29.8) 0.834 181/400 (45.2) b0.001
35/46 (76.1) 28/46 (60.9) 8/46 (17.4) 1/46 (2.2) 3/46 (6.5) 0/46 (0) 2/46 (4.3)
250/390 (64.1) 105/392 (26.8) 41/392 (10.5) 30/392 (7.7) 45/391 (11.5) 19/392 (4.8) 7/392 (1.8)
0.106 b0.001 0.158 0.231 0.306 0.243 0.247
Clinical manifestations Renal involvement Lung involvement Cardiac involvement Hepatic involvement Peripheral vessel thrombosis Cerebral involvement Skin involvement Gastrointestinal tract involvement Splenic involvement Adrenal gland involvement
29/46 (63.0) 29/46 (63.0) 27/46 (57.4) 19/46 (40.4) 24/46 (52.2) 22/46 (47.8) 17/46 (37.0) 8/46 (17.4) 7/46 (15.2) 3/46 (6.5)
296/399 (74.2) 233/399 (58.4) 193/397 (48.6) 144/399 (36.1) 136/396 (34.3) 226/398 (56.8) 185/399 (46.4) 99/399 (24.8) 67/398 (16.8) 44/398 (11.1)
0.107 0.544 0.252 0.559 0.017 0.247 0.225 0.265 0.781 0.453
Laboratory features Lupus anticoagulant IgG aCL IgM aCL IgG anti-β2-glycoprotein I IgM anti-β2-glycoprotein I
33/42 (78.6) 29/40 (72.5) 16/35 (45.7) 5/6 (83.3) 3/5 (60.0)
279/340 (82.1) 301/365 (82.5) 150/310 (48.4) 37/47 (78.7) 9/23 (39.1)
0.582 0.123 0.764 1.000 0.624
Treatment Anticoagulants (ACs) Corticosteroids (CS) Plasma exchange (PE) Intravenous immunoglobulins (IVIG) Cyclophosphamide ACs + CS + PE or IVIG Mortality
35/45 (77.8) 34/45 (75.6) 18/45 (40.0) 17/45 (37.8) 11/45 (24.4) 12/45 (26.7) 12/46 (26.1)
327/386 (84.7) 297/387 (76.7) 133/387 (34.4) 98/387 (25.3) 98/387 (25.3) 81/386 (21.0) 160/398 (40.2)
0.230 0.669 0.522 0.091 0.835 0.426 0.063
Sex (female/male) Primary APS SLE Catastrophic APS as the first manifestation of APS Precipitating factors Infection Malignancy Oral contraceptive Surgery Medications SLE flare
p
Values are expressed as number of patients with positive result/number of patients tested (%). Abbreviations: aCL, anticardiolipin antibodies; APS, antiphospholipid syndrome; SLE, systemic lupus erythematosus.
Among the 46 cases with pediatric catastrophic APS, 12 (26.1%) died at the time of the catastrophic event. We found no significant differences between patients who died and those who survived in terms of the demographic characteristics, the prevalence of precipitating factors, first clinical manifestation at the time of catastrophic event, main clinical organ involvement during the catastrophic event or laboratory features (Table 4). Additionally, no differences were detected considering the individual or combined treatments used during the catastrophic episode. Notably, all patients who received the combination of ACs + CS + PE and/or IVIG survived the catastrophic event; however this difference was not statistically significant (0% versus 24.2%; p = 0.087) (Table 4). 3.5. Comparison between pediatric and adult patients with catastrophic APS There were minimal differences in the demographic and clinical characteristics, laboratory features, and treatment between pediatric and adult patients with catastrophic APS (Table 2). The distribution by sex and diagnosis was similar, with a preponderance of females (71% in pediatric versus 69% in adult patients) and patients with primary APS (67.4% in pediatric versus 59.7% in adult patients). Interestingly, catastrophic APS was the first manifestation of APS in a higher number of pediatric patients (86.6% versus 45.2%, p b 0.001). Another important
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Table 3 Treatment used during the 43 episodes of pediatric catastrophic APS⁎. No. (%) of CAPS episodes treated Individual treatments ACs CS CYC PE IVIG AGs Treatment combinations ACs + CS ACs + CS + CYC + PE + IVIG + AGs ACs + CS + PE and/or IVIG ACs + CS + CYC ACs + CS + PE + IVIG ACs + CS + IVIG CS alone CS + PE ACs + PE ACs + CS + CYC + PE ACs + CS + CYC + PE + IVIG AC + PE + IVIG ACs alone ACs + CS + AGs IVIG alone CS + IVIG ACs + CS + PE ACs + CS + CYC + IVIG AC + CS + CYC + IVIG + AGs + fibrinolysis PE + fibrinolysis ACs + IVIG PE alone
35/43 (81.4) 34/43 (79.1) 11/43 (25.6) 18/43 (41.9) 17/43 (39.5) 3/43 (7.0)
9/43 (20.9) 8/43 (18.6) 5/43 (11.6) 4/43 (9.3) 4/43 (9.3) 3/43 (7.0) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3)
Abbreviations: ACs, anticoagulants; AGs, antiaggregants; CAPS, catastrophic antiphospholipid syndrome; CS, corticosteroids; CYC, cyclophosphamide; IVIG, intravenous immunoglobulin; PE, plasma exchange. ⁎ Treatment was not recorded for one patient and in 2 other patients, none of these treatments were given.
point is that infections were more prevalent as precipitating factor for catastrophic event in pediatric patients (60.9% versus 26.8%, p b 0.001). Considering the clinical organ involvement during catastrophic episode, the only significant difference was the higher prevalence of peripheral vessel thrombosis in pediatric patients (52.2% versus 34.3%, p = 0.017) (Table 2). Kidney was the organ most frequently involved in both groups of patients. The prevalence of patients presenting catastrophic APS recurrence was similar between the two groups of patients (2.2% versus 2.5%). Mortality was lower in the pediatric patients but without statistically significant difference (26.1% versus 40.2%; odds ratio [OR], 1.9; 95% confidence interval [CI] 0.96–3.79; p = 0.063). 3.6. Comparison between pediatric patients with classic and catastrophic APS Given the recently published review of 121 pediatric patients with classic APS [8], we tried to compare the main demographic characteristics, clinical data, and laboratory features among pediatric patients with classic APS and those with catastrophic APS. Unfortunately, due to the characteristic multi-organ involvement of catastrophic APS, some data such as clinical manifestations are not fully comparable between the two groups of patients. In other cases, the limited presentation of the data such as the absence of SD of mean age of presentation at the time of classic APS hindered their comparison. In general terms, the distribution by sex was similar. Noteworthy, the prevalence of primary APS (49.5% versus 67.4%, p = 0.032) and of an identifiable precipitating factor (23.1% versus 76.1%, p b 0.001) was higher in patients with catastrophic APS. In addition, infections were more prevalent in patients with pediatric catastrophic APS (9.9% versus 60.9%, p b 0.001).
Table 4 Demographic characteristics, precipitating factors, laboratory features, and treatment in patients with pediatric catastrophic APS, categorized according to their death or survival. Patients who died (n = 12)
Patients who survived (n = 33)
p
Demographics Sex, no. female/no. male Age (mean ± SD)
10/2 10.9 ± 6.2
22/11 11.8 ± 4.0
0.460 0.592
Diagnosis Primary APS SLE
7 (58.3) 4 (33.3)
24 (70.6) 9 (26.5)
0.488 0.717
Precipitating factors Infection Surgery Oral contraceptives CAPS as the first manifestation of APS
9 (75.0) 7 (58.3) 1 (8.3) 1 (8.3) 11 (91.7)
26 (76.5) 21 (61.8) 2 (5.8) 0 (0) 27 (79.4)
1 1 1 0.261 0.66
Laboratory features Hemolysis Thrombocytopenia Schistocytes Antinuclear antibodies Antiphospholipid antibodies IgG aCL IgM aCL Lupus anticoagulant
4/10 (40.0) 10/12 (83.3) 2/8 (25.0) 5/7 (71.4)
6/28 (21.4) 21 (65.6) 4/24 (16.7) 10/24 (41.7)
0.404
8/10 (80.0) 3/8 (37.5) 6/10 (60.0)
21/30 (70.0) 13/27 (48.1) 27/32 (84.4)
0.696 0.700 0.181
Treatment ACs CS PE IVIG Cyclophosphamide ACs + CS + PE and/or IVIG
7/12 (58.3) 7/12 (58.3) 3/12 (25.0) 3/12 (25.0) 3/12 (25.0) 0/12 (0)
28/33 (84.8) 27/33 (81.8) 15/33 (45.5) 14/33 (42.4) 8/33 (24.2) 8/33 (24.2)
0.101 0.131 0.308 0.488 1 0.087
0.625 0.220
Values are the number of patients/number tested (%). Abbreviations: aCL, anticardiolipin antibodies; ACs, anticoagulants; APS, antiphospholipid syndrome; CAPS, catastrophic APS; CS, corticosteroids; IVIG, intravenous immunoglobulin; PE, plasma exchange; SLE, systemic lupus erythematosus.
Considering the immunologic features, isolated IgG and IgM isotypes of aCL were more prevalent in pediatric patients with catastrophic variant of APS (35% versus 72.5%, p b 0.001 for isolated IgG aCL and 17% versus 45.7% for isolated IgM aCL, p b 0.001), respectively. The prevalence of LAC and aCL was similar within the two groups of patients.
4. Discussion In the current study we have demonstrated that the clinical, laboratory and treatment features between the pediatric and adult patients with catastrophic APS were generally similar. The main differences between the two groups of patients were the higher prevalence of infections as precipitating factor for catastrophic event and of peripheral vessel thrombosis in the pediatric population, and the fact that catastrophic APS was the first manifestation of APS in a higher number of pediatric patients. Interestingly, pediatric patients showed a lower mortality although this difference was not statistically significant. The higher prevalence of catastrophic APS as a first manifestation of APS in pediatric patients may be explained by their young age, which prevented them from developing thrombosis or obstetric morbidity before the development of catastrophic event. Considering the precipitating factors, infections were more prevalent in pediatric patients with catastrophic APS compared with adult patients with catastrophic event (60.9% versus 26.8%, p b 0.001). In addition, infections were more prevalent in pediatric catastrophic APS patients compared with pediatric patients with classic APS as well (60.9% versus 9.9%, p b 0.001). In a previous review of 100 patients with APS associated with infections, 40% of them developed a catastrophic variant of APS.
H. Berman et al. / Autoimmunity Reviews 13 (2014) 157–162
Overall, the mean age at the time of APS in this review was 32 ± 18 years, and there were 24 patients under 18 years [9]. The reason for these differences is not clear. One possible explanation could be the fact that, among the different precipitating factors, infection is presented with a higher prevalence in childhood, compared with neoplasia, surgery or medications. Actually, children are more likely to be in contact with infectious agents that could play an important role through the molecular mimicry process in the development of thrombotic storm that characterizes the catastrophic APS [10]. In fact, the antigenic similarity between infectious microorganisms and natural anticoagulants might result in an immune response producing antiphospholipid antibodies [11,12]. It is possible that some specific polymorphisms of toll-like receptors and other molecules involved in this immune response might be responsible for the development of catastrophic variant of APS in children [13,14]. Regarding clinical manifestations, the prevalence of involvement of several organs was very similar among pediatric and adult patients with catastrophic APS. The only difference was the higher prevalence of peripheral vessel thrombosis in the pediatric population. The organs most frequently involved were kidneys, lungs, heart and brain and the most frequent clinical manifestations were renal failure (47.8%), heart failure (39.1%), deep venous thrombosis (41.3%), and acute respiratory distress syndrome (28.3%). There were no differences neither in the laboratory features nor in the immunologic profile between the two groups of patients. Of note, thrombocytopenia was one of the main hallmarks of pediatric catastrophic APS, present in 70.5% of patients. Anticoagulant therapy and CS were the two main treatments used in pediatric catastrophic APS. Almost 20% of patients received the combined treatment with ACs + CS + PE and/or IVIG that has been related to a higher survival in patients with catastrophic APS in general [4]. In terms of mortality, 12 (26.1%) patients died at the time of the catastrophic event. When patients who died and those who survived were compared, we did not find prognostic factors considering demographic characteristics, precipitating factors, clinical manifestations, and laboratory features. Interestingly, none of the patients who received the combination of ACs + CS + PE and/or IVIG died during the catastrophic event but the difference was not statistically significant (0% versus 24.2%; p = 0.087). One important point could be the difference in mortality between pediatric and adult patients with catastrophic APS. The former showed a trend for a lower mortality (26.1% versus 40.2%, OR 1.9, 95% CI 0.96– 3.79; p = 0.063), but without statistical significance. It could be possible that in a larger sample of pediatric patients the difference would be higher and statistically significant. The major limitation of our study was inherent to the CAPS Registry. One of the main sources of information of this international registry is the periodic search of published catastrophic APS reports. In some published cases clinical aspects, the treatment or the long-term follow-up of patients with catastrophic APS have not been described in detail. In this sense, the accuracy of the clinical diagnosis as judged by the attending physician and the attribution of some clinical manifestations such as encephalopathy, seizures or myocardiopathy to the antiphospholipid antibodies are points to keep in mind. In addition, the detection of antiphospholipid antibodies was performed by different laboratory techniques with the consequent variability of results. In spite of these limitations, our study represents the first picture of pediatric patients with catastrophic APS. 5. Conclusion The current study is the first description of pediatric patients with catastrophic APS, corresponding to 10% of patients included in the CAPS Registry. The clinical and laboratory features, and treatment between catastrophic APS in pediatric patients and those cases in adults were similar. Catastrophic APS was the first manifestation of APS in a
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higher number of pediatric patients. In addition, infections as precipitating factor and peripheral vessel thrombosis were more frequent in the pediatric population. Of note, pediatric patients showed a trend for a lower mortality although the difference was not statistically significant. Further analysis with a larger number of pediatric patients is necessary to confirm these preliminary findings. Despite its limitations, the information from the CAPS Registry is so far the only valuable tool to increase the knowledge of this rare and intriguing disease. Take-home messages • There is no information about catastrophic antiphospholipid syndrome of patients in the pediatric age. • The current study is the first description of pediatric patients with catastrophic APS, corresponding to 10% of patients included in the CAPS Registry. • There were minimal differences in the clinical and laboratory features, and treatment between catastrophic APS in pediatric patients and those cases in adults. Appendix. The Catastrophic Antiphospholipid Syndrome Registry Project Group (European Forum on Antiphospholipid Antibodies) Coordinators: R. Cervera, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; G. Espinosa, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; I. Rodríguez-Pintó, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; D. Erkan, Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, USA; Y. Shoenfeld, Sheba Medical Centre, Tel-Hashomer, Israel. Members: M. Abu-Shakra, Department of Medicine D, Soroka Medical Center, Beersheba, Israel; N.E. Aikawa, Pediatric Rheumatology Unit, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil; A. Allievi, Department of Internal Medicine and Autoimmune Diseases, Hospital Fernandez, Buenos Aires, Argentina; M.-C. Amigo, Rheumatology Department, Instituto Nacional de Cardiología, Mexico City, Mexico; L. Barile-Fabris, Rheumatology Department, Hospital de Especialidades, Centro Medico la Raza IMSS, Mexico City, Mexico; J.-J. Boffa, Department of Nephrology, Hôpital Tenon, Paris, France; M.-C. Boffa, Hôpital Pitié-Salpêtrière, Paris, France; I. Chávez, Mexico City, Mexico; J. Chapman, Neuroimmunology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; C. Davidson, Department of Cardiology, Royal Sussex Hospital, Brighton, UK; E. de Meis, Department of Hematology, National Cancer Institute, Rio de Janeiro, Brazil; A.E. Denes, Division of Oncology, Department of Medicine, Louis, USA; S. Derenne, CHU Nantes, France; R.H.W.M. Derksen, Department of Rheumatology and Clinical Immunology, University Medical Centre, Utrecht, The Netherlands; J.F. Diaz Coto, Caja Costarricense del Seguro Social, San Jose, Costa Rica; P. Disdier, Service de Medecine Interne, Centre Hospitalier Universitaire Timone, Marseille, France; R.M. Egan, Department of Medicine, University of Kentucky Medical Center, Lexington, USA; M. Ehrenfeld, Chaim Sheba Medical Center and Tel-Aviv University, Tel-Hashomer, Israel; R. Enriquez, Nephrology Section, Hospital General de Elx, Spain; F. Falcini, Department of Paediatrics, University of Florence, Italy; L.S. Fang, Renal Associates, Massachusetts General Hospital and Harvard Medical School, Boston, USA; J. Freire de Carvalho, Rheumatology Division, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil; M. García-Carrasco, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico; J.A. Gomez-Puerta, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; J.T. Grandone, Neenah, Wisconsin, USA; S. Gregory, Department of Hematology, National Cancer Institute, Rio de Janeiro, Brazil; A. Gurjal, Division of Hematology/Oncology, Barbara Ann
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Karmanos Cancer Institute, Detroit, Michigan, USA; G. Hayem, Department of Rheumatology, CHU Bichat-Claude-Bernard, Paris, France; G.R.V. Hughes, Lupus Research Unit, The Rayne Institute, St. Thomas' Hospital, London, UK; S. Inam, Riyadh Armed Forces Hospital Riyadh, Saudi Arabia; K.S. Kant, Department of Internal Medicine, University of Cincinnati College of Medicine, Ohio, USA; M.A. Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK; C.S. Kitchens, Department of Medicine, University of Florida, Gainesville, USA; M.J. Kupferminc, Department of Obstetrics and Gynaecology, Lis Maternity Hospital, Tel Aviv, Israel; G. de Larrañaga, Hospital Muñiz, Buenos Aires, Argentina; R.A. Levy, Department of Rheumatology, Faculdade de Ciencias Medicas, Rio de Janeiro, Brazil; M.D. Lockshin, Hospital for Special Surgery, New York, USA; S.F. Lui, Department of Medicine, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong; P.J. Maddison, Gwynedd Rheumatology Service, Ysbyty Gwynedd, Bangor, UK; C.E. Maia Rodrigues, Rheumatology Division, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil; Y.A. Mekori, Department of Medicine, Meir Hospital, Kfar Saba, Israel; S. Menahem, Department of Renal Medicine, Alfred Hospital, Melbourne, Australia; T. Miyamae, Department of Paediatrics, Yokohama City University School of Medicine, Yokohama, Japan; J. Moore, Department of Haematology, St. Vincent's Hospital, Sydney, Australia; H.M. Moutsopoulos, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; F.J. MuñozRodríguez, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; J. Musial, Jagiellonian University School of Medicine, Krakow, Poland; A. Nakajima, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan; M.C. Neuwelt, Medical Service, VA Palo Alto Health Care System, USA; M. Niedzwiecki, Medical University of Gdansk, Poland; A. Parke, Department of Internal Medicine, Division of Rheumatic Diseases, University of Connecticut Health Center, Connecticut, USA; S. Praprotnik, University Clinical Center, Department of Rheumatology, Ljubljana, Slovenia; B. Roca, Department of Internal Medicine, Hospital General de Castelló, Castelló, Spain; J. Rojas-Rodriguez, Department of Rheumatology, Specialties Hospital, Manuel Avila Camacho National Medical Centre, Puebla, Mexico; R. Roldan, Rheumatology Department, Hospital Reina Sofia, Cordoba, Spain; A.D. Sawitzke, Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, USA; C.G. Schaar, Department of Haematology, Leiden University Medical Centre, The Netherlands; A. Sipek-Dolnicar, Department of Rheumatology, University Medical Center, Ljubljana, Slovenia; J.
Springer, Medical University of Gdansk, Poland; A.C. Spyropoulos, Clinical Thrombosis Center, Albuquerque, New Mexico, USA; R. Sinico, Nephrology and Dialysis Unit and Center of Clinical Immunology and Rheumatology, San Carlo Borromeo Hospital, Milan, Italy; L. Stojanovich, Clinical Center “Bezhanijska Kosa”, Belgrade, Serbia and Montenegro; D. Tan, Singapore General Hospital, Singapore; M. Tektonidou, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; C. Vasconcelos, Hospital General de San Antonio, Porto, Portugal; M.P. Veloso, Hospital Universitario Clementino Fraga Filho, Rio de Janeiro, Brazil; M. Wislowska, Outpatient Department of Rheumatology, Central Clinical Hospital, Warsaw, Poland; J. Yinh, Tufts — New England Medical Centre, Boston, USA; W. You, Department of Obstetrics and Gynecology, National Naval Medical Center, Bethesda, USA. References [1] Erkan D, Espinosa G, Cervera R. Catastrophic antiphosholipid syndrome. Updated diagnostic algorithms. Autoimmun Rev 2010;10:74–9. [2] Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992;19:508–12. [3] Cervera R. CAPS Registry. Lupus 2012;21:755–7. [4] Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum 2006;54:2568–76. [5] Asherson RA, Cervera R, de Groot PR, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [6] Cervera R, Font J, Gómez-Puerta JA, et al. Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis 2005;64:1205–9. [7] Amador-Patarroyo MJ, Rodriguez-Rodriguez A, Montoya-Ortiz G. How does age at onset influences the outcome of autoimmune diseases? Autoimmun Dis 2012;2012:251730. [8] Avcin T, Cimaz R, Silverman ED, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry. Pediatrics 2008;122:e1100–7. [9] Cervera R, Asherson RA, Acevedo ML, et al. Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients. Ann Rheum Dis 2004;63:1312–7. [10] Asherson RA, Shoenfeld Y. The role of infection in the pathogenesis of catastrophic antiphospholipid syndrome. Molecular mimicry? J Rheumatol 2000;27:12–4. [11] Blank M, Krause I, Fridkin M, et al. Bacterial induction of autoantibodies to beta2glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 2002;109:797–804. [12] Sène D, Piette JC, Cacoub P. Antiphospholipid antibodies, antiphospholipid syndrome and infections. Autoimmun Rev 2008;4:272–7. [13] Martin E, Winn R, Nugen K. Catastrophic antiphospholipid syndrome in a community-acquired methicilin-resistant Staphylococcus aureus infection: a review of pathogenesis with a case for molecular mimicry. Autoimmun Rev 2011;10:181–8. [14] Harper BE, Willis R, Pierangeli SS. Pathophysiological mechanisms in antiphospholipid syndrome. Int J Clin Rheumatol 2011;6:157–71.
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Pediatric catastrophic antiphospholipid syndrome: Descriptive analysis of 45 patients from the “CAPS Registry” Horacio Berman a,1, Ignasi Rodríguez-Pintó a,1, Ricard Cervera a, Simone Gregory b, Ernesto de Meis b, Carlos Ewerton Maia Rodrigues c, Nádia Emi Aikawa c,d, Jozélio Freire de Carvalho c, Janusz Springer e, Maciej Niedzwiecki e, Gerard Espinosa a,⁎, on behalf of the Catastrophic Registry Project Group (European Forum on Antiphospholipid Antibodies) 2 a
Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Catalonia, Spain Department of Hematology, National Cancer Institute, Rio de Janeiro, Brazil c Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil d Pediatric Rheumatology Unit, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil e Medical University of Gdansk, Poland b
a r t i c l e
i n f o
Article history: Received 1 October 2013 Accepted 13 October 2013 Available online 19 October 2013 Keywords: Catastrophic antiphospholipid syndrome Antiphospholipid syndrome Pediatric Infant
a b s t r a c t Given the lack of information about catastrophic antiphospholipid syndrome (APS) in pediatric patients, the objective of the current study was to describe the clinical characteristics, laboratory features, treatment, and outcome of pediatric patients with catastrophic APS and compare them with the adult patients with catastrophic APS. We identified patients who were under 18 years of age at time of catastrophic APS diagnosis included in the international registry of patients with catastrophic APS (CAPS Registry). Their main demographic and clinical characteristics, laboratory features, treatment, and outcome were described and compared with those of adult patients with catastrophic APS. From the 446 patients included in the CAPS Registry as of May 2013, 45 (10.3%) patients developed 46 catastrophic events before 18 years of age (one patient presented two episodes). Overall, 32 (71.1%) patients were female and the mean age was 11.5 ± 4.6 years (range, 3 months–18 years). A total of 31 (68.9%) patients suffered from primary APS and 13 (28.9%) from systemic lupus erythematosus (SLE). The main differences between the two groups of patients were the higher prevalence of infections as precipitating factor for catastrophic event in the pediatric population (60.9% versus 26.8% in the adult population, p b 0.001) and of peripheral vessel thrombosis (52.2% versus 34.3%, p = 0.017). In addition, catastrophic APS was the first manifestation of APS more frequently in pediatric patients (86.6% versus 45.2%, p b 0.001). Interestingly, pediatric patients showed a trend of lower mortality, although the difference was not statistically significant (26.1% versus 40.2%; odds ratio, 1.9; 95% confidence interval, 0.96–3.79; p = 0.063). No differences were found neither in the laboratory features nor in the isolated or combination treatments between groups. Catastrophic APS in pediatric patients is a rare disease. There are minimal differences in the clinical and laboratory features, treatment, and outcome of pediatric and adult catastrophic APS patients. © 2013 Elsevier B.V. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . 2.1. Data collection . . . . . . . . . . . . . . 2.2. Statistical analysis . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . 3.1. General characteristics . . . . . . . . . . . 3.2. Precipitating factors and clinical presentation
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⁎ Corresponding author at: Servei de Malalties Autoimmunes, Hospital Clínic, Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail address: [email protected] (G. Espinosa). 1 These two authors contributed equally to this study. 2 See complete list of members at the appendix at the end of article. 1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2013.10.004
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3.3. APS-related laboratory findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Treatment and outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Comparison between pediatric and adult patients with catastrophic APS . . . . . . . . . . . . . . . . . . . . . . 3.6. Comparison between pediatric patients with classic and catastrophic APS . . . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix. The Catastrophic Antiphospholipid Syndrome Registry Project Group (European Forum on Antiphospholipid Antibodies) References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The catastrophic antiphospholipid syndrome (APS) is characterized by multi-organ thrombosis developing over a short period of time [1]. This life-threatening variant of the APS that represents less than 1% of all patients with APS, was first described more than 20 years ago [2]. Since then, more than 400 cases have been collected in the catastrophic APS international registry (CAPS Registry). This registry was created by the European Forum on Antiphospholipid Antibodies, a study group devoted to the development of multi-center projects with large populations of APS patients [3]. The analysis of this registry has generated a cluster of knowledge of the main clinical, and laboratory features as well as the outcome of patients with catastrophic APS [4]. In addition, classification criteria and treatment guidelines for its management have been established [1,5,6]. Age at onset might modulate the clinical expression and prognosis of patients with different autoimmune diseases [7]. Particularly for classic APS, a review of 121 patients with pediatric APS, defined as the onset of APS before the patient's 18th birthday, demonstrated some important differences between the pediatric and adult APS patients [8]. In fact, the high female preponderance in adult patients (female/male ratio of 5:1) with classic APS does not occur in the pediatric subset (1.2:1). Deep venous thrombosis in the legs was the most frequent venous thrombotic event both in pediatric and adult APS patients (40% versus 32%, respectively). However, cerebral sinus venous thrombosis and ischemic stroke as a first manifestation of APS were significantly more frequent in the pediatric APS patients. In addition, the presence of lupus anticoagulant (LAC) was also more frequent in patients with pediatric APS [8]. In the present article, we describe the clinical characteristics, laboratory features, and outcomes of patients who presented with catastrophic APS in the pediatric age and compared them with those of adult patients with catastrophic APS.
2. Patients and methods 2.1. Data collection We identified the patients with catastrophic APS in the pediatric age included in the CAPS Registry, the website-based international registry of patients with catastrophic APS. The sources of information for the CAPS Registry are: a) periodic Medline search of published catastrophic APS reports; and b) personal communication with physicians in charge of catastrophic APS patients for the unpublished cases (physicians fill out a standardized data form collecting demographic, clinical, therapeutic, and outcome information) [3]. The registry documents the clinical, laboratory and therapeutic data of all reported cases of catastrophic APS which can be freely consulted through the website (http://infmed.fcrb.es/en/web/caps). Patients were considered as having pediatric catastrophic APS if the onset of catastrophic episode occurred before 18 years of age. Data from these patients were summarized in a standardized data-form, including sex, age and diagnosis of the underlying disease, precipitating factors,
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main thrombotic clinical features, laboratory findings, treatment, disease evolution and final outcome.
2.2. Statistical analysis Results from continuous variables are presented as mean ± standard deviation (SD) and categorical data as percentages. Comparisons were performed using the Mann–Whitney test for continuous variables, whereas Fisher's exact test was used for categorical variables. Differences were considered significant when p b 0.05.
3. Results 3.1. General characteristics From the 446 patients included in the CAPS Registry since May 2013, 45 (10.3%) patients developed 46 catastrophic events before 18 years of age (one patient presented two episodes). Overall, 32 (71.1%) patients were female and the mean age was 11.5 ± 4.6 years (range, 3 months–18 years) (Table 1). A total of 31 (68.9%) patients suffered from primary APS, 13 (28.9%) from systemic lupus erythematosus (SLE) and one from a lupus-like disease (2.2%).
3.2. Precipitating factors and clinical presentation Precipitating factors were identified in 35 (76.1%) events. Infection was the most frequent precipitating factor found in 28 (60.9%) of them, followed by neoplasia (8; 17.4%), surgery (3; 6.5%), and SLE flares (2; 4.3%), whereas oral contraceptives and Cesarean section accounted for once case each (2.2%). In the remaining case, the precipitating factor was not specified. In nine events, two concomitant precipitating factors were identified. The catastrophic event appeared as the first manifestation of APS in 86.7% of cases. The clinical characteristics of patients with pediatric catastrophic APS are summarized in Table 1. Kidney manifestations were present in 29 (63.0%) episodes and mainly consisted of renal failure, arterial hypertension, and proteinuria. Lung involvement appeared in 29 (63.0%) cases in the form of acute respiratory distress syndrome and pulmonary embolism. Cardiac involvement was present in 27 (57.4%) episodes and included cardiac failure, myocardial infarction and heart valve lesions. Cerebral involvement was also frequent, present in 22 (47.8%) cases, and included encephalopathy, cerebrovascular accidents and seizures. Liver involvement and peripheral venous thrombosis appeared in 19 (40.4%) cases each. The skin was involved in 17 (37.0%) episodes presenting as livedo reticularis, skin ulcers, cutaneous necrosis, gangrene, digital ischemia and purpura. Raynaud's phenomenon was not reported. The gastrointestinal tract was involved in 8 (17.4%) episodes, spleen infarcts were described in 7 (15.2%) and adrenal gland involvement was reported in 3 cases (6.5%). Involvement of bone marrow, peripheral nervous system, pancreas, and eye occurred in less than 5% of patients.
H. Berman et al. / Autoimmunity Reviews 13 (2014) 157–162 Table 1 Demographic features and clinical manifestations of 46 episodes from 45 patients with pediatric catastrophic APS.
Table 2 Comparison of demographic and clinical characteristics, precipitating factors, treatment and mortality between pediatric and adult patients with catastrophic APS.
N (%) Demographics Sex (female/male) Age at the time of pediatric catastrophic APS (years)
32/13 (71/29) 11.5 ± 4.6
Diagnosis Primary APS Systemic lupus erythematosus Systemic lupus erythematosus-like Catastrophic APS as the first manifestation of APS
32 (69.6) 13 (28.3) 1 (2.2) 39 (86.7)
Clinical manifestations Kidney involvement Renal failure Arterial hypertension Proteinuria Lung involvement Acute respiratory distress syndrome Pulmonary embolism Alveolar hemorrhage Heart involvement Heart failure Heart valve disease Myocardial infarction Peripheral vessel thrombosis Venous Arterial Brain involvement Encephalopathy Cerebrovascular accident Seizures Liver involvement Hepatitis Liver failure Skin involvement Livedo reticularis Ulcers Skin necrosis Digital ischemia Purpura Gastrointestinal tract involvement Spleen involvement Adrenal gland involvement
29 (63.0) 22 (47.8) 11 (23.9) 6 (13.3) 29 (63.0) 13 (28.3) 6 (13.0) 2 (4.3) 27 (58.7) 18 (39.1) 2 (4.3) 2 (4.3) 24 (52.2) 19 (41.3) 11 (23.9) 22 (47.8) 10 (21.7) 6 (13.0) 5 (10.9) 19 (41.3) 11 (23.9) 2 (4.3) 17 (37.0) 9 (19.6) 5 (10.9) 5 (10.9) 5 (10.9) 3 (6.5) 8 (17.4) 7 (15.2) 3 (6.5)
Age at the time of catastrophic APS is expressed as mean ± standard deviation. Abbreviations: APS, antiphospholipid syndrome.
3.3. APS-related laboratory findings Thrombocytopenia (≤100,000/mm3) was found in 31/44 (70.5%) cases of pediatric catastrophic APS. The LAC was reported as positive in 78.6% of patients, followed by the IgG isotype of anticardiolipin antibodies (aCL) in 72.5% and the IgM isotype of aCL in 45.7% of them. The IgG isotype of anti-β2-glycoprotein I antibodies was positive in 5/6 patients (83.3%) and the IgM isotype in 3/5 (60.0%) patients. Antinuclear and anti-DNA antibodies were positive in 15/31 (48.4%) and in 13/30 (43.3%) cases, respectively. Six (13.0%) events presented with schistocytes. Unfortunately, no data of disseminated intravascular coagulation were specified. 3.4. Treatment and outcome Anticoagulants (ACs) were the most frequent treatment used in 35 of the 45 (77.8%) cases of pediatric catastrophic APS, followed by corticosteroids (CS) in 34 (75.6%), plasma exchange (PE) in 18 (40.0%), intravenous immunoglobulins (IVIG) in 17 (37.8%), cyclophosphamide in 11 (24.4%) and platelet aggregation inhibitors in 3 (7.0%) (Table 2). Most patients received a combination of therapies. ACs + CS was the most common combination (20.9%), followed by ACs + CS + PE and/ or IVIGs (18.6%), and ACs + CS + cyclophosphamide + PE and/or IVIG (11.6%) (Table 3). Data on treatment were not available in one patient.
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Pediatric cases N (%)
Adult cases N (%)
32/13 (71/29) 31/46 (67.4) 13/46 (28.3) 38/46 (86.6)
267/121 (69/31) 0.752 232/400 (59.7) 0.220 119/400 (29.8) 0.834 181/400 (45.2) b0.001
35/46 (76.1) 28/46 (60.9) 8/46 (17.4) 1/46 (2.2) 3/46 (6.5) 0/46 (0) 2/46 (4.3)
250/390 (64.1) 105/392 (26.8) 41/392 (10.5) 30/392 (7.7) 45/391 (11.5) 19/392 (4.8) 7/392 (1.8)
0.106 b0.001 0.158 0.231 0.306 0.243 0.247
Clinical manifestations Renal involvement Lung involvement Cardiac involvement Hepatic involvement Peripheral vessel thrombosis Cerebral involvement Skin involvement Gastrointestinal tract involvement Splenic involvement Adrenal gland involvement
29/46 (63.0) 29/46 (63.0) 27/46 (57.4) 19/46 (40.4) 24/46 (52.2) 22/46 (47.8) 17/46 (37.0) 8/46 (17.4) 7/46 (15.2) 3/46 (6.5)
296/399 (74.2) 233/399 (58.4) 193/397 (48.6) 144/399 (36.1) 136/396 (34.3) 226/398 (56.8) 185/399 (46.4) 99/399 (24.8) 67/398 (16.8) 44/398 (11.1)
0.107 0.544 0.252 0.559 0.017 0.247 0.225 0.265 0.781 0.453
Laboratory features Lupus anticoagulant IgG aCL IgM aCL IgG anti-β2-glycoprotein I IgM anti-β2-glycoprotein I
33/42 (78.6) 29/40 (72.5) 16/35 (45.7) 5/6 (83.3) 3/5 (60.0)
279/340 (82.1) 301/365 (82.5) 150/310 (48.4) 37/47 (78.7) 9/23 (39.1)
0.582 0.123 0.764 1.000 0.624
Treatment Anticoagulants (ACs) Corticosteroids (CS) Plasma exchange (PE) Intravenous immunoglobulins (IVIG) Cyclophosphamide ACs + CS + PE or IVIG Mortality
35/45 (77.8) 34/45 (75.6) 18/45 (40.0) 17/45 (37.8) 11/45 (24.4) 12/45 (26.7) 12/46 (26.1)
327/386 (84.7) 297/387 (76.7) 133/387 (34.4) 98/387 (25.3) 98/387 (25.3) 81/386 (21.0) 160/398 (40.2)
0.230 0.669 0.522 0.091 0.835 0.426 0.063
Sex (female/male) Primary APS SLE Catastrophic APS as the first manifestation of APS Precipitating factors Infection Malignancy Oral contraceptive Surgery Medications SLE flare
p
Values are expressed as number of patients with positive result/number of patients tested (%). Abbreviations: aCL, anticardiolipin antibodies; APS, antiphospholipid syndrome; SLE, systemic lupus erythematosus.
Among the 46 cases with pediatric catastrophic APS, 12 (26.1%) died at the time of the catastrophic event. We found no significant differences between patients who died and those who survived in terms of the demographic characteristics, the prevalence of precipitating factors, first clinical manifestation at the time of catastrophic event, main clinical organ involvement during the catastrophic event or laboratory features (Table 4). Additionally, no differences were detected considering the individual or combined treatments used during the catastrophic episode. Notably, all patients who received the combination of ACs + CS + PE and/or IVIG survived the catastrophic event; however this difference was not statistically significant (0% versus 24.2%; p = 0.087) (Table 4). 3.5. Comparison between pediatric and adult patients with catastrophic APS There were minimal differences in the demographic and clinical characteristics, laboratory features, and treatment between pediatric and adult patients with catastrophic APS (Table 2). The distribution by sex and diagnosis was similar, with a preponderance of females (71% in pediatric versus 69% in adult patients) and patients with primary APS (67.4% in pediatric versus 59.7% in adult patients). Interestingly, catastrophic APS was the first manifestation of APS in a higher number of pediatric patients (86.6% versus 45.2%, p b 0.001). Another important
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Table 3 Treatment used during the 43 episodes of pediatric catastrophic APS⁎. No. (%) of CAPS episodes treated Individual treatments ACs CS CYC PE IVIG AGs Treatment combinations ACs + CS ACs + CS + CYC + PE + IVIG + AGs ACs + CS + PE and/or IVIG ACs + CS + CYC ACs + CS + PE + IVIG ACs + CS + IVIG CS alone CS + PE ACs + PE ACs + CS + CYC + PE ACs + CS + CYC + PE + IVIG AC + PE + IVIG ACs alone ACs + CS + AGs IVIG alone CS + IVIG ACs + CS + PE ACs + CS + CYC + IVIG AC + CS + CYC + IVIG + AGs + fibrinolysis PE + fibrinolysis ACs + IVIG PE alone
35/43 (81.4) 34/43 (79.1) 11/43 (25.6) 18/43 (41.9) 17/43 (39.5) 3/43 (7.0)
9/43 (20.9) 8/43 (18.6) 5/43 (11.6) 4/43 (9.3) 4/43 (9.3) 3/43 (7.0) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 2/43 (4.7) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3) 1/43 (2.3)
Abbreviations: ACs, anticoagulants; AGs, antiaggregants; CAPS, catastrophic antiphospholipid syndrome; CS, corticosteroids; CYC, cyclophosphamide; IVIG, intravenous immunoglobulin; PE, plasma exchange. ⁎ Treatment was not recorded for one patient and in 2 other patients, none of these treatments were given.
point is that infections were more prevalent as precipitating factor for catastrophic event in pediatric patients (60.9% versus 26.8%, p b 0.001). Considering the clinical organ involvement during catastrophic episode, the only significant difference was the higher prevalence of peripheral vessel thrombosis in pediatric patients (52.2% versus 34.3%, p = 0.017) (Table 2). Kidney was the organ most frequently involved in both groups of patients. The prevalence of patients presenting catastrophic APS recurrence was similar between the two groups of patients (2.2% versus 2.5%). Mortality was lower in the pediatric patients but without statistically significant difference (26.1% versus 40.2%; odds ratio [OR], 1.9; 95% confidence interval [CI] 0.96–3.79; p = 0.063). 3.6. Comparison between pediatric patients with classic and catastrophic APS Given the recently published review of 121 pediatric patients with classic APS [8], we tried to compare the main demographic characteristics, clinical data, and laboratory features among pediatric patients with classic APS and those with catastrophic APS. Unfortunately, due to the characteristic multi-organ involvement of catastrophic APS, some data such as clinical manifestations are not fully comparable between the two groups of patients. In other cases, the limited presentation of the data such as the absence of SD of mean age of presentation at the time of classic APS hindered their comparison. In general terms, the distribution by sex was similar. Noteworthy, the prevalence of primary APS (49.5% versus 67.4%, p = 0.032) and of an identifiable precipitating factor (23.1% versus 76.1%, p b 0.001) was higher in patients with catastrophic APS. In addition, infections were more prevalent in patients with pediatric catastrophic APS (9.9% versus 60.9%, p b 0.001).
Table 4 Demographic characteristics, precipitating factors, laboratory features, and treatment in patients with pediatric catastrophic APS, categorized according to their death or survival. Patients who died (n = 12)
Patients who survived (n = 33)
p
Demographics Sex, no. female/no. male Age (mean ± SD)
10/2 10.9 ± 6.2
22/11 11.8 ± 4.0
0.460 0.592
Diagnosis Primary APS SLE
7 (58.3) 4 (33.3)
24 (70.6) 9 (26.5)
0.488 0.717
Precipitating factors Infection Surgery Oral contraceptives CAPS as the first manifestation of APS
9 (75.0) 7 (58.3) 1 (8.3) 1 (8.3) 11 (91.7)
26 (76.5) 21 (61.8) 2 (5.8) 0 (0) 27 (79.4)
1 1 1 0.261 0.66
Laboratory features Hemolysis Thrombocytopenia Schistocytes Antinuclear antibodies Antiphospholipid antibodies IgG aCL IgM aCL Lupus anticoagulant
4/10 (40.0) 10/12 (83.3) 2/8 (25.0) 5/7 (71.4)
6/28 (21.4) 21 (65.6) 4/24 (16.7) 10/24 (41.7)
0.404
8/10 (80.0) 3/8 (37.5) 6/10 (60.0)
21/30 (70.0) 13/27 (48.1) 27/32 (84.4)
0.696 0.700 0.181
Treatment ACs CS PE IVIG Cyclophosphamide ACs + CS + PE and/or IVIG
7/12 (58.3) 7/12 (58.3) 3/12 (25.0) 3/12 (25.0) 3/12 (25.0) 0/12 (0)
28/33 (84.8) 27/33 (81.8) 15/33 (45.5) 14/33 (42.4) 8/33 (24.2) 8/33 (24.2)
0.101 0.131 0.308 0.488 1 0.087
0.625 0.220
Values are the number of patients/number tested (%). Abbreviations: aCL, anticardiolipin antibodies; ACs, anticoagulants; APS, antiphospholipid syndrome; CAPS, catastrophic APS; CS, corticosteroids; IVIG, intravenous immunoglobulin; PE, plasma exchange; SLE, systemic lupus erythematosus.
Considering the immunologic features, isolated IgG and IgM isotypes of aCL were more prevalent in pediatric patients with catastrophic variant of APS (35% versus 72.5%, p b 0.001 for isolated IgG aCL and 17% versus 45.7% for isolated IgM aCL, p b 0.001), respectively. The prevalence of LAC and aCL was similar within the two groups of patients.
4. Discussion In the current study we have demonstrated that the clinical, laboratory and treatment features between the pediatric and adult patients with catastrophic APS were generally similar. The main differences between the two groups of patients were the higher prevalence of infections as precipitating factor for catastrophic event and of peripheral vessel thrombosis in the pediatric population, and the fact that catastrophic APS was the first manifestation of APS in a higher number of pediatric patients. Interestingly, pediatric patients showed a lower mortality although this difference was not statistically significant. The higher prevalence of catastrophic APS as a first manifestation of APS in pediatric patients may be explained by their young age, which prevented them from developing thrombosis or obstetric morbidity before the development of catastrophic event. Considering the precipitating factors, infections were more prevalent in pediatric patients with catastrophic APS compared with adult patients with catastrophic event (60.9% versus 26.8%, p b 0.001). In addition, infections were more prevalent in pediatric catastrophic APS patients compared with pediatric patients with classic APS as well (60.9% versus 9.9%, p b 0.001). In a previous review of 100 patients with APS associated with infections, 40% of them developed a catastrophic variant of APS.
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Overall, the mean age at the time of APS in this review was 32 ± 18 years, and there were 24 patients under 18 years [9]. The reason for these differences is not clear. One possible explanation could be the fact that, among the different precipitating factors, infection is presented with a higher prevalence in childhood, compared with neoplasia, surgery or medications. Actually, children are more likely to be in contact with infectious agents that could play an important role through the molecular mimicry process in the development of thrombotic storm that characterizes the catastrophic APS [10]. In fact, the antigenic similarity between infectious microorganisms and natural anticoagulants might result in an immune response producing antiphospholipid antibodies [11,12]. It is possible that some specific polymorphisms of toll-like receptors and other molecules involved in this immune response might be responsible for the development of catastrophic variant of APS in children [13,14]. Regarding clinical manifestations, the prevalence of involvement of several organs was very similar among pediatric and adult patients with catastrophic APS. The only difference was the higher prevalence of peripheral vessel thrombosis in the pediatric population. The organs most frequently involved were kidneys, lungs, heart and brain and the most frequent clinical manifestations were renal failure (47.8%), heart failure (39.1%), deep venous thrombosis (41.3%), and acute respiratory distress syndrome (28.3%). There were no differences neither in the laboratory features nor in the immunologic profile between the two groups of patients. Of note, thrombocytopenia was one of the main hallmarks of pediatric catastrophic APS, present in 70.5% of patients. Anticoagulant therapy and CS were the two main treatments used in pediatric catastrophic APS. Almost 20% of patients received the combined treatment with ACs + CS + PE and/or IVIG that has been related to a higher survival in patients with catastrophic APS in general [4]. In terms of mortality, 12 (26.1%) patients died at the time of the catastrophic event. When patients who died and those who survived were compared, we did not find prognostic factors considering demographic characteristics, precipitating factors, clinical manifestations, and laboratory features. Interestingly, none of the patients who received the combination of ACs + CS + PE and/or IVIG died during the catastrophic event but the difference was not statistically significant (0% versus 24.2%; p = 0.087). One important point could be the difference in mortality between pediatric and adult patients with catastrophic APS. The former showed a trend for a lower mortality (26.1% versus 40.2%, OR 1.9, 95% CI 0.96– 3.79; p = 0.063), but without statistical significance. It could be possible that in a larger sample of pediatric patients the difference would be higher and statistically significant. The major limitation of our study was inherent to the CAPS Registry. One of the main sources of information of this international registry is the periodic search of published catastrophic APS reports. In some published cases clinical aspects, the treatment or the long-term follow-up of patients with catastrophic APS have not been described in detail. In this sense, the accuracy of the clinical diagnosis as judged by the attending physician and the attribution of some clinical manifestations such as encephalopathy, seizures or myocardiopathy to the antiphospholipid antibodies are points to keep in mind. In addition, the detection of antiphospholipid antibodies was performed by different laboratory techniques with the consequent variability of results. In spite of these limitations, our study represents the first picture of pediatric patients with catastrophic APS. 5. Conclusion The current study is the first description of pediatric patients with catastrophic APS, corresponding to 10% of patients included in the CAPS Registry. The clinical and laboratory features, and treatment between catastrophic APS in pediatric patients and those cases in adults were similar. Catastrophic APS was the first manifestation of APS in a
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higher number of pediatric patients. In addition, infections as precipitating factor and peripheral vessel thrombosis were more frequent in the pediatric population. Of note, pediatric patients showed a trend for a lower mortality although the difference was not statistically significant. Further analysis with a larger number of pediatric patients is necessary to confirm these preliminary findings. Despite its limitations, the information from the CAPS Registry is so far the only valuable tool to increase the knowledge of this rare and intriguing disease. Take-home messages • There is no information about catastrophic antiphospholipid syndrome of patients in the pediatric age. • The current study is the first description of pediatric patients with catastrophic APS, corresponding to 10% of patients included in the CAPS Registry. • There were minimal differences in the clinical and laboratory features, and treatment between catastrophic APS in pediatric patients and those cases in adults. Appendix. The Catastrophic Antiphospholipid Syndrome Registry Project Group (European Forum on Antiphospholipid Antibodies) Coordinators: R. Cervera, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; G. Espinosa, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; I. Rodríguez-Pintó, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; D. Erkan, Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, USA; Y. Shoenfeld, Sheba Medical Centre, Tel-Hashomer, Israel. Members: M. Abu-Shakra, Department of Medicine D, Soroka Medical Center, Beersheba, Israel; N.E. Aikawa, Pediatric Rheumatology Unit, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil; A. Allievi, Department of Internal Medicine and Autoimmune Diseases, Hospital Fernandez, Buenos Aires, Argentina; M.-C. Amigo, Rheumatology Department, Instituto Nacional de Cardiología, Mexico City, Mexico; L. Barile-Fabris, Rheumatology Department, Hospital de Especialidades, Centro Medico la Raza IMSS, Mexico City, Mexico; J.-J. Boffa, Department of Nephrology, Hôpital Tenon, Paris, France; M.-C. Boffa, Hôpital Pitié-Salpêtrière, Paris, France; I. Chávez, Mexico City, Mexico; J. Chapman, Neuroimmunology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; C. Davidson, Department of Cardiology, Royal Sussex Hospital, Brighton, UK; E. de Meis, Department of Hematology, National Cancer Institute, Rio de Janeiro, Brazil; A.E. Denes, Division of Oncology, Department of Medicine, Louis, USA; S. Derenne, CHU Nantes, France; R.H.W.M. Derksen, Department of Rheumatology and Clinical Immunology, University Medical Centre, Utrecht, The Netherlands; J.F. Diaz Coto, Caja Costarricense del Seguro Social, San Jose, Costa Rica; P. Disdier, Service de Medecine Interne, Centre Hospitalier Universitaire Timone, Marseille, France; R.M. Egan, Department of Medicine, University of Kentucky Medical Center, Lexington, USA; M. Ehrenfeld, Chaim Sheba Medical Center and Tel-Aviv University, Tel-Hashomer, Israel; R. Enriquez, Nephrology Section, Hospital General de Elx, Spain; F. Falcini, Department of Paediatrics, University of Florence, Italy; L.S. Fang, Renal Associates, Massachusetts General Hospital and Harvard Medical School, Boston, USA; J. Freire de Carvalho, Rheumatology Division, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil; M. García-Carrasco, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico; J.A. Gomez-Puerta, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; J.T. Grandone, Neenah, Wisconsin, USA; S. Gregory, Department of Hematology, National Cancer Institute, Rio de Janeiro, Brazil; A. Gurjal, Division of Hematology/Oncology, Barbara Ann
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Karmanos Cancer Institute, Detroit, Michigan, USA; G. Hayem, Department of Rheumatology, CHU Bichat-Claude-Bernard, Paris, France; G.R.V. Hughes, Lupus Research Unit, The Rayne Institute, St. Thomas' Hospital, London, UK; S. Inam, Riyadh Armed Forces Hospital Riyadh, Saudi Arabia; K.S. Kant, Department of Internal Medicine, University of Cincinnati College of Medicine, Ohio, USA; M.A. Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK; C.S. Kitchens, Department of Medicine, University of Florida, Gainesville, USA; M.J. Kupferminc, Department of Obstetrics and Gynaecology, Lis Maternity Hospital, Tel Aviv, Israel; G. de Larrañaga, Hospital Muñiz, Buenos Aires, Argentina; R.A. Levy, Department of Rheumatology, Faculdade de Ciencias Medicas, Rio de Janeiro, Brazil; M.D. Lockshin, Hospital for Special Surgery, New York, USA; S.F. Lui, Department of Medicine, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong; P.J. Maddison, Gwynedd Rheumatology Service, Ysbyty Gwynedd, Bangor, UK; C.E. Maia Rodrigues, Rheumatology Division, Instituto da Criança, Hospital das Clinicas da Facultade de Medicina da Universidade de Sao Paulo, SP, Brazil; Y.A. Mekori, Department of Medicine, Meir Hospital, Kfar Saba, Israel; S. Menahem, Department of Renal Medicine, Alfred Hospital, Melbourne, Australia; T. Miyamae, Department of Paediatrics, Yokohama City University School of Medicine, Yokohama, Japan; J. Moore, Department of Haematology, St. Vincent's Hospital, Sydney, Australia; H.M. Moutsopoulos, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; F.J. MuñozRodríguez, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; J. Musial, Jagiellonian University School of Medicine, Krakow, Poland; A. Nakajima, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan; M.C. Neuwelt, Medical Service, VA Palo Alto Health Care System, USA; M. Niedzwiecki, Medical University of Gdansk, Poland; A. Parke, Department of Internal Medicine, Division of Rheumatic Diseases, University of Connecticut Health Center, Connecticut, USA; S. Praprotnik, University Clinical Center, Department of Rheumatology, Ljubljana, Slovenia; B. Roca, Department of Internal Medicine, Hospital General de Castelló, Castelló, Spain; J. Rojas-Rodriguez, Department of Rheumatology, Specialties Hospital, Manuel Avila Camacho National Medical Centre, Puebla, Mexico; R. Roldan, Rheumatology Department, Hospital Reina Sofia, Cordoba, Spain; A.D. Sawitzke, Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, USA; C.G. Schaar, Department of Haematology, Leiden University Medical Centre, The Netherlands; A. Sipek-Dolnicar, Department of Rheumatology, University Medical Center, Ljubljana, Slovenia; J.
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