SciELO - Scientific Electronic Library Online

 
vol.58Characterization of scrotal involvement in children and adolescents with IgA vasculitisFactors associated with ASDAS remission in a long-term study of ankylosing spondylitis patients under tumor necrosis factor inhibitors author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

  • text new page (beta)
  • English (pdf)
  • Article in xml format
  • How to cite this article
  • SciELO Analytics
  • Curriculum ScienTI
  • Automatic translation

Indicators

Related links

Share


Advances in Rheumatology

On-line version ISSN 2523-3106

Adv. rheumatol. vol.58  São Paulo  2018  Epub July 29, 2019

http://dx.doi.org/10.1186/s42358-018-0038-4 

Research

Diffuse alveolar hemorrhage in childhoodonset systemic lupus erythematosus: a severe disease flare with serious outcome

Gabriela Blay1  2 

Joaquim C. Rodrigues2 

Juliana C. O. Ferreira1 

Gabriela N. Leal1 

Natali W. Gormezano3 

Glaucia V. Novak1 

Rosa M. R. Pereira3 

Maria T. Terreri4 

Claudia S. Magalhães5 

Beatriz C. Molinari1 

Ana P. Sakamoto4 

Nadia E. Aikawa1  3 

Lucia M. A. Campos1 

Taciana A. P. Fernandes5 

Gleice Clemente4 

Octavio A. B. Peracchi4 

Vanessa Bugni4 

Roberto Marini6 

Silvana B. Sacchetti7 

Luciana M. Carvalho8 

Melissa M. Fraga9 

Tânia C. M. Castro10 

Valéria C. Ramos11 

Eloisa Bonfá1 

Clovis A. Silva1  2  * 
http://orcid.org/0000-0001-9250-6508

Brazilian Childhood-onset Systemic Lupus Erythematosus Group

1Pediatric Rheumatology Unit, Children's Institute, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Av. Dr. Eneas Carvalho Aguiar, 647 Cerqueira César, São Paulo, SP 05403-000, Brazil

2Pediatric Pulmonology Unit, Children's Institute, FMUSP, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP 05403-000, Brazil

3Division of Rheumatology, FMUSP, Sao Paulo, Brazil

4Pediatric Rheumatology Unit, Universidade Federal de São Paulo, Sao Paulo, Brazil

5São Paulo State University (UNESP), Faculdade de Medicina de Botucatu, Sao Paulo, Brazil

6São Paulo State University of Campinas (UNICAMP), Sao Paulo, Brazil

7Irmandade da Santa Casa de Misericórdia de São Paulo, Sao Paulo, Brazil

8Ribeirão Preto Medical School – University of São Paulo, Sao Paulo, Brazil

9Hospital Darcy Vargas, Sao Paulo, Brazil

10Hospital Menino Jesus, Sao Paulo, Brazil

11Pontifical Catholic University of Sorocaba, Sao Paulo, Brazil


Abstract

Objective:

To evaluate prevalence, clinical manifestations, laboratory abnormalities and treatment in a multicenter cohort study including 847 childhood-onset systemic lupus erythematosus (cSLE) patients with and without diffuse alveolar hemorrhage (DAH), as well as concomitant parameters of severity.

Methods:

DAH was defined as the presence of at least three respiratory symptoms/signs associated with diffuse interstitial/alveolar infiltrates on chest x-ray or high-resolution computer tomography and sudden drop in hemoglobin levels. Statistical analysis was performed using Bonferroni correction (p < 0.0022).

Results:

DAH was observed in 19/847 (2.2%) cSLE patients. Cough/dyspnea/tachycardia/hypoxemia occurred in all cSLE patients with DAH. Concomitant parameters of severity observed were: mechanical ventilation in 14/19 (74%), hemoptysis 12/19 (63%), macrophage activation syndrome 2/19 (10%) and death 9/19 (47%). Further analysis of cSLE patients at DAH diagnosis compared to 76 cSLE control patients without DAH with same disease duration [3 (1–151) vs. 4 (1–151) months, p = 0.335], showed higher frequencies of constitutional involvement (74% vs. 10%, p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and sepsis (53% vs. 9%, p < 0.0001) in the DAH group. The median of disease activity score(SLEDAI-2 K) was significantly higher in cSLE patients with DAH [18 (5–40) vs. 6 (0–44), p < 0.0001]. The frequencies of thrombocytopenia (53% vs. 12%, p < 0.0001), intravenous methylprednisolone (95% vs. 16%, p < 0.0001) and intravenous cyclophosphamide (47% vs. 8%, p < 0.0001) were also significantly higher in DAH patients.

Conclusions:

This was the first study to demonstrate that DAH, although not a disease activity score descriptor, occurred in the context of significant moderate/severe cSLE flare. Importantly, we identified that this condition was associated with serious disease flare complicated by sepsis with high mortality rate.

Keywords: Diffuse alveolar hemorrhage; Childhood; Systemic lupus erythematosus; Multicenter study

Introduction

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by the involvement of several organs and systems [13]. Pleuropulmonary manifestations were described as initial feature from 17 to 42% childhood-onset SLE (cSLE) patients, particularly mild to moderate pleuritis [1, 35]. These respiratory complications may be classified as acute or chronic [6].

Of note, diffuse alveolar hemorrhage (DAH) is an acute, rare and life-threatening pulmonary manifestation characterized by sudden onset of respiratory symptoms, such as dyspnea; hypoxemia; hemoptysis; tachycardia and/or cough; associated with new lung infiltrates on chest x-ray (CXR) or high-resolution computer tomography (HRCT); and sudden drop in serum hemoglobin levels [7, 8].

Data of DAH in cSLE patients are limited due to the small representation of this complication in previous case series or the focus on the comparison to adult SLE, precluding an accurate analysis of associated factors and outcomes in patients with and without this severe complication [4, 715].

Therefore, the objective of the present multicenter cohort study was to assess the prevalence and the possible DAH association with demographic, clinical manifestations, laboratory abnormalities, disease activity score, treatments and outcomes in a large cSLE population.

Methods

This was a retrospective multicenter cohort study including 1017 patients followed in 10 Pediatric Rheumatology tertiary referral services in São Paulo state, Brazil. One hundred and sixty five patients were excluded due to: incomplete medical charts (n = 96), undifferentiated connective tissue disorder with 3 or fewer American College of Rheumatology (ACR) criteria (n = 43), isolated cutaneous lupus erythematosus (n = 11), neonatal lupus erythematosus (n = 8), drug-induced lupus (n = 5) and mixed connective tissue disease (n = 2). Therefore, this study group comprised 852 cSLE patients. All of them fulfilled the ACR criteria for SLE [16], with disease onset before the age of 18 [17].

An investigator meeting was held for protocol training according to the clinical parameters definitions and disease activity tool scoring, as previously reported [3, 18]. Patient's medical charts were systematically reviewed according to demographic data, clinical characteristics, DAH features, laboratorial abnormalities, therapies and outcomes.

DAH was defined as the presence of at least three respiratory symptoms and signs (dyspnea, hypoxemia, hemoptysis, tachycardia and/or cough) associated with diffuse interstitial and/or alveolar infiltrates on CXR or HRCT, and sudden drop in hemoglobin level at least of 1.5 g/dL [7, 10, 11]. Bronchoalveolar lavage with hemosiderin-laden macrophages evidence was also recorded [14]. Patients were divided in two groups with similar disease duration: cSLE patients with DAH (assessed at DAH diagnosis) and cSLE patients without DAH (assessed at last visit).

Descriptors and definitions of SLE Disease Activity Index 2000 (SLEDAI-2 K) score were used to characterize disease parameters and to calculate disease activity score [19]. Custom definitions were defined as previously reported [3, 18]. Neuropsychiatric lupus included 19 syndromes according to ACR classification criteria [20]. Antiphospholipid syndrome was diagnosed taking into account the presence of arterial and/or venous thrombosis concomitant to high titers of anti-phospholipid antibodies [21]. Macrophage activation syndrome was diagnosed considering the preliminary cSLE diagnostic guidelines, requiring the presence of at least one clinical plus two laboratorial criteria [22].

Laboratorial assessment included complete blood cell count and urine test. Anti-double-stranded DNA (anti-dsDNA), IgG and IgM anticardiolipin antibodies (aCL) were carried out at each center and the cutoff values were considered valid. Lupus anticoagulant was detected according to the guidelines of the International Society on Thrombosis and Hemostasis [23].

Drug treatment data (prednisone, intravenous methylprednisolone, chloroquine diphosphate, hydroxychloroquine sulfate, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, intravenous cyclophosphamide and intravenous gammaglobulin) were also recorded.

Statistical analysis

Results were presented as an absolute number (frequency) for categorical variables and median (range) or mean ± standard deviation (SD) for continuous variables. Categorical variables comparisons were assessed by Pearson χ-Square or Fisher's exact test. Continuous variables from cSLE patients with and without DAH were compared by Mann-Whitney test or t test as appropriate. Statistical analysis was performed using Bonferroni correction (p < 0.0022).

Results

DAH was observed in 19/847 (2.2%) cSLE patients. Cough, dyspnea, tachycardia and hypoxemia occurred in all 19 cSLE patients with DAH; hemoptysis in 12/19 and endotracheal tube bleeding in 14/19. New infiltrates on CXR or HRCT and hemoglobin drop at least of 1.5 g/dL were evidenced in all cSLE patients with DAH (Table 1). Bronchoalveolar lavage was performed in two cSLE patients and hemosiderin-laden macrophage was observed in both of them.

Table 1 Demographic, clinical manifestations and imaging in 19 childhood-onset systemic lupus erythematosus (cSLE) patients with diffuse alveolar hemorrhage 

Patient Disease duration, Months Cough Dyspnoea Tachycardia Hypoxemia Hemoptysis/bleeding in endotracheal tube New Infiltrates Drop Hbg/dL CXR or HRCT
1 60 + + + + + / + + 1.8
2 151 + + + + + / + + 1.5
3 5 + + + + + / + + 2.0
4 0 + + + + + / + + 1.6
5 33 + + + + + / + + 1.9
6 0 + + + + + / + + 2.7
7 3 + + + + + / + + 1.7
8 90 + + + + + / - + 2.5
9 42 + + + + + / + + 4.5
10 4 + + + + + / + + 3.0
11 0 + + + + -/- + 3.2
12 47 + + + + -/+ + 1.5
13 5 + + + + -/+ + 1.5
14 0 + + + + + / - + 2.0
15 0 + + + + -/+ + 7.0
16 0 + + + + -/- + 2.0
17 3 + + + + -/+ + 2.0
18 1 + + + + -/- + 1.7
19 0 + + + + + / + + 8.0

CXR Chest x-ray, HRCT High resolution computer tomography, Hb Hemoglobulin, ND Not done

Regarding outcomes, hospitalization in pediatric intensive care unit occurred in 17/19 cSLE patients with DAH and mechanical ventilation in 14/19. DAH associated with sepsis was observed in 10/19 cSLE patients. Concomitant macrophage activation syndrome was evidenced in 2/19 patients. Death was observed in 9/19 cSLE patients. The median duration between DAH onset and death was 2 days (0.5–25). Blood erythrocyte trans-fusion and broad-spectrum antibiotics were administered in all cSLE patients with DAH. Intravenous methylprednisolone pulse therapy was used in 18/19 cSLE and intravenous cyclophosphamide in 9/19 (Table 2). None of them had recurrence of DAH.

Table 2 Outcomes and immunosuppressive treatment in 19 childhood-onset systemic lupus erythematosus (cSLE) patients with diffuse alveolar hemorrhage 

Patient ICU Mechanical ventilation Sepsis MAS Death IV methylprednisolone pulse therapy IV cyclophosphamide
1 + + + + +
2 + + + + +
3 + + + + +
4 + + + + +
5 + + + +
6 + + + +
7 + + + + + +
8 + + + + +
9 + + + +
10 + + + +
11 + +
12 + + + + +
13 + + +
14 + + + +
15 + + + + + +
16 + +
17 + + + + +
18 +
19 + + + +

ICU Intensive care unit, MAS Macrophage activation syndrome, IV Intravenous

Further comparison between cSLE patients with DAH compared to 76 cSLE control patients without DAH with same disease duration [3 (1–151) vs. 4 (1–151) months, p = 0.335], showed significantly higher frequencies of constitutional involvement (74% vs. 10%, p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and sepsis (53% vs. 9%, p < 0.0001) in the former group. The median of SLEDAI-2 K was significantly higher in cSLE patients with DAH compared to cSLE patients without this complication [18 (5–40) vs. 6 (0–44), p < 0.0001]. Frequencies of nephritis and neuropsychiatric involvements were similar in both groups (p > 0.0022) (Table 3).

Table 3 Demographic data, clinical manifestations and disease activity score in childhood-onset systemic lupus erythematosus (cSLE) patients according to the presence of diffuse alveolar hemorrhage (DAH) 

Variables With DAH (at diagnosis) (n = 19) Without DAH (at last visit) (n = 76) P
Demographic data
Female gender 14 (74) 66 (87) 0.172
Disease duration, months 3(1–151) 4(1–151) 0.335
Current age, years 13 (9–18) 13 (3–23) 0.889
Current clinical manifestations
Constitutional 14 (74) 8(10) < 0.0001*
Mucocutaneous 9(47) 31 (41) 0.614
Musculoskeletal 5(26) 8(10) 0.127
Serositis 12 (63) 5(6) < 0.0001*
Neuropsychiatric 4(21) 11 (14) 0.491
Nephritis 16 (84) 42 (55) 0.033
Current autoimmune thrombosis (APS), n= 90 0/16 (0) 1/74 (1) 1.000
Sepsis 10 (53) 7(9) <0.0001*
Macrophage activation syndrome 2(10) 2(3) 0.113
Death, n = 94 9(47) 15/75 (20) 0.020
Current disease activity
SLEDAI-2 K, n=82 18(5–40) 6(0–44) < 0.0001*

*P-value according to Bonferroni correction for multiple comparisons (p < 0.0022). Results are presented in n (%) and median (range), APS Antiphospholipid syndrome, SLEDAI-2 K Systemic Lupus Erythematosus Disease Activity Index 2000

The frequencies of thrombocytopenia (53% vs. 12%, p < 0.0001), intravenous methylprednisolone (95% vs. 16%, p < 0.0001) and intravenous cyclophosphamide (47% vs. 8%, p < 0.0001) were also significantly higher in the former group. The median of prednisone dose was higher in cSLE patients with DAH compared to those without DAH [1.4 (0.3–2) vs. 0.5 (0.03–3) mg/Kg, p < 0.0001] (Table 4).

Table 4 Current laboratory tests and drug therapy of childhood-onset systemic lupus erythematosus (cSLE) according to the presence of diffuse alveolar hemorrhage (DAH) 

Variables With DAH (at diagnosis) (n = 19) Without DAH (at last visit) (n = 76) P
Current laboratory exams
Autoimmune hemolytic anemia 5(26) 8(10) 0.127
Thrombocytopenia, < 150,000/mm3, n = 93 10 (52) 9/74 (12) < 0.0001*
Anti-ds-DNA,n= 75 8/13 (61) 30/62 (48) 0.544
Drug therapy
Prednisone current dose, mg/Kg, n= 82 1.4 (0.3–2) 0.5 (0.03–3) < 0.0001*
Intravenous methylprednisolone 18 (95) 12 (15) < 0.0001*
Antimalarial drugs 14 (74) 41 (54) 0.193
Azathioprine 2(10) 16 (21) 0.513
Mycophenolate mofetil 1(5) 5(6) 1.000
Intravenous cyclophosphamide 9(47) 6(8) < 0.0001*

*P-value according to Bonferroni correction for multiple comparisons (p < 0.0022). Results are presented in n (%) and median (range), anti-ds-DNA – anti-doublestranded DNA antibodies

Discussion

This is the largest study to evaluate DAH, a rare and acute life-threatening pulmonary manifestation, in cSLE population.

The multicenter study design with a large cohort of children and adolescents patients allowed a more precise assessment of this rare and severe cSLE respiratory complication. An investigator meeting was also taken in place to standardize the protocol study in all centers. However, the limitation was the retrospective design with potential missing data.

The prevalence of DAH in cSLE patients in the present study was similar to other reports, varying from 2 to 5% [6, 7, 24]. Diagnosis of this condition included the typical respiratory symptoms and signs, drop in hemoglobin levels and the radiographic evidence of pulmonary infiltrates, as well as the assessment of hypoxemia due to acute respiratory distress [7]. In addition, in two of our cSLE patients the presence of haemosiderin-laden macrophages in the absence of bloody fluid suggested recent bleeding [6], analyzed by the bronchoalveolar lavage.

We demonstrated that DAH, although not a disease activity score descriptor of SLEDAI-2 K [19], was associated with high moderate or severe disease activity scores, particularly thrombocytopenia, serositis and constitutional involvement. In contrast to previous reports DAH was not associated with lupus nephritis [13].

Of note, we identified that DAH was a severe manifestation requiring pediatric intensive care unit hospitalization and mechanical ventilation for the vast majority of our patients. We extended previous observation of high frequency of severe infection in adults/cSLE patients with DAH [7], thus demonstrating the catastrophic nature of DAH, since more than half of cSLE patients developed concomitant sepsis.

Reinforcing this finding of poor outcome, 10% of the cSLE patients were diagnosed with concomitant macrophage activation syndrome. In fact, this is a rare condition characterized by an excessive activation and proliferation of T lymphocytes and macrophages with massive hypersecretion of proinflammatory cytokines, and may induce severe hemorraghae [25, 26].

We observed a high mortality rate in cSLE patients with DAH, as also observed in other studies [6, 10, 11]. This unfavorable outcome revealed that sepsis and macrophage activation syndrome may have contributed to the death of more than half of the patients.

Early detection of this severe pulmonary complication, prompt immunosuppressive agents treatment [9, 15, 27], empirical antibiotics and mechanical ventilation are therefore essential to improve cSLE outcome [6, 7].

Conclusion

This was the first study to demonstrate that DAH, although not a disease activity score descriptor, occurs in the context of significant moderate/severe cSLE flare. Importantly, we identified that this condition is associated with serious disease flare complicated by sepsis and high mortality rate.

Funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 301805/2013–0 to RMRP, 303752/2015–7 to MTT, 301479/2015–1 to CSM, 305068/2014–8 to EB and 303422/2015–7 to CAS), Federico Foundation (to EB, RMRP and CAS) and by Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

This study was approved by our Ethics Committee.

Consent for publication

Not applicable.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

Our gratitude to Ulysses Doria-Filho for the statistical analysis. The authors thank the following Pediatric Rheumatology Divisions and colleagues for including their patients: Children's Institute, FMUSP (Marco F. Silva, Mariana Ferriani, Roberta C. Gomes, Victor L. Marques, Gabriella E. Lube, Sandra R. M. Lopes, Glaucia V. Novak, Beatriz C. Molinari, Clarissa C. Valões, Verena Balbi, João D. Montoni, Laila P. Coelho, Luciana S. Henriques, Pedro Anuardo, Monica Verdier, Juliana B. Brunelli, Adriana A. Jesus, Antonio C. Pastorino, Heloisa H. Marques, Andrea Watanabe, Benita G. Schvartsman, Maria H. Vaisbich, Werther B. Carvalho, Magda Carneiro-Sampaio, Vicente Odone-Filho); Division of Rheumatology, FMUSP (Juliane A. Paupitz, Glauce L. Lima, Ana Paula L. Assad); UNIFESP (Maria O. E. Hilário, Andreia S. Lopes, Aline Alencar, Daniela P. Piotto, Giampaolo Faquin); UNESP (Priscila R. Aoki, Juliana O. Sato, Silvana P. Cardin); Irmandade da Santa Casa de Misericórdia de São Paulo (Andressa Guariento, Eunice Okuda, Maria Carolina dos Santos); UNICAMP (Maraísa Centeville, Renata Barbosa, Simone Appenzeller); Ribeirão Preto Medical School, FMUSP (Paola P. Kahwage, Gecilmara Pileggi, Francisco Hugo Gomes, Virginia Ferriani), Hospital Infantil Darcy Vargas (Jonatas Libório, Cássia Barbosa, Luciana T. P. Paulo); Hospital Municipal Infantil Menino Jesus (Simone Lotufo).

References

1. Silva CA. Childhood-onset systemic lupus erythematosus: early disease manifestations that the paediatrician must know. Expert Rev Clin Immunol. 2016;12:907–10. [ Links ]

2. Silva CA, Aikawa NE, Pereira RM, Campos LM. Management considerations for childhood-onset systemic lupus erythematosus patients and implications on therapy. Expert Rev Clin Immunol. 2016;12:301–13. [ Links ]

3. Gomes RC, Silva MF, Kozu K, Bonfá E, Pereira RM, Terreri MT, et al. Features of 847 childhood-onset systemic lupus Erythematousus patients in three age groups at diagnosis: a Brazilian multicenter study. Arthritis Care Res (Hoboken). 2016;68:1736–41. [ Links ]

4. Veiga CS, Coutinho DS, Nakaie CM, Campos LM, Suzuki L, Cunha MT, et al. Subclinical pulmonary abnormalities in childhood-onset systemic lupus erythematosus patients. Lupus. 2016;25:645–51. [ Links ]

5. Bader-Meunier B, Armengaud JB, Haddad E, Salomon R, Deschênes G, Koné-Paut I, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr. 2005;146:648–53. [ Links ]

6. Richardson AE, Warrier K, Vyas H. Respiratory complications of the rheumatological diseases in childhood. Arch Dis Child. 2016;101:752–8. [ Links ]

7. Araujo DB, Borba EF, Silva CA, Campos LM, Pereira RM, Bonfa E, et al. Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus. Lupus. 2012;21:872–7. [ Links ]

8. Singla S, Canter DL, Vece TJ, Muscal E, DeGuzman M. Diffuse Alveolar Hemorrhage as a Manifestation of Childhood-Onset Systemic Lupus Erythematosus. Hosp Pediatr. 2016;6:496–500. [ Links ]

9. Godfrey S. Pulmonary hemorrhage/hemoptysis in children. Pediatr Pulmonol. 2004;37:476–84. [ Links ]

10. Liu MF, Lee JH, Weng TH, Lee YY. Clinical experience of 13 cases with severe pulmonary hemorrhage in systemic lupus erythematosus with active nephritis. Scand J Rheumatol. 1998;27:291–5. [ Links ]

11. Chang MY, Fang JT, Chen YC, Huang CC. Diffuse alveolar hemorrhage in systemic lupus erythematosus: a single center retrospective study in Taiwan. Ren Fail. 2002;24:791–802. [ Links ]

12. Koh WH, Thumboo J, Boey ML. Pulmonary haemorrhage in oriental patients with systemic lupus erythematosus. Lupus. 1997;6:713–6. [ Links ]

13. Shen M, Zeng X, Tian X, Zhang F, Zeng X, Zhang X, et al. Diffuse alveolar hemorrhage in systemic lupus erythematosus: a retrospective study in China. Lupus. 2010;19:1326–30. [ Links ]

14. Martinez-Martinez MU, Sturbaum AK, Alcocer-Varela J, Merayo-Chalico J, Gómez-Martin D, Gómez-Bañuelos Jde J, et al. Factors associated with mortality and infections in patients with systemic lupus erythematosus with diffuse alveolar hemorrhage. J Rheumatol. 2014;41:1656–61. [ Links ]

15. Kimura D, Shah S, Briceno-Medina M, Sathanandam S, Haberman B, Zhang J, et al. Management of massive diffuse alveolar hemorrhage in a child with systemic lupus erythematosus. J Intensive Care. 2015;7(3):10. [ Links ]

16. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erhytematosus. Arthrits Rheum. 1997;40:1725. [ Links ]

17. Silva CA, Avcin T, Brunner HI. Taxonomy for systemic lupus erythematosus with onset before adulthood. Arthritis Care Res (Hoboken). 2012;64:1787–93. [ Links ]

18. Marques VL, Gormezano NW, Bonfá E, Aikawa NE, Terreri MT, Pereira RM, et al. Pancreatitis subtypes survey in 852 childhood-onset systemic lupus erythematosus patients. J Pediatr Gastroenterol Nutr. 2016;62:328–34. [ Links ]

19. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288–91. [ Links ]

20. American College of Rheumatology Ad Hoc committee on neuropsychiatric Lupus Syndromes. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42:599–608. [ Links ]

21. Avcin T, Cimaz R, Rozman B. The Ped-APS Registry: the antiphospholipid syndrome in childhood. Lupus. 2009;18:894–9. [ Links ]

22. Parodi A, Davì S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S, et al. Lupus Working Group of the Paediatric Rheumatology European Society. A macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum. 2009;60:3388–99. [ Links ]

23. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and standardisation committee of the ISTH. Thromb Haemost. 1995;74:1185–90. [ Links ]

24. Fatemi A, Matinfar M, Saber M, Smiley A. The association between initial manifestations of childhood-onset systemic lupus erythematosus and the survival. Int J Rheum Dis. 2016;19:974–80. in press. [ Links ]

25. Gormezano NW, Otsuzi CI, Barros DL, da Silva MA, Pereira RM, Campos LM, et al. Macrophage activation syndrome: A severe and frequent manifestation of acute pancreatitis in 362 childhood-onset compared to 1830 adult-onset systemic lupus erythematosus patients. Semin Arthritis Rheum. 2016;45:706–10. [ Links ]

26. Aikawa NE, Carvalho JF, Bonfá E, Lotito AP, Silva CA. Macrophage activation syndrome associated with etanercept in a child with systemic onset juvenile idiopathic arthritis. Isr Med Assoc J. 2009;11:635–6. [ Links ]

27. Klumb EM, Silva CA, Lanna CC, Sato EI, Borba EF, Brenol JC, et al. Consensus of the Brazilian Society of Rheumatology for the diagnosis, management and treatment of lupus nephritis. Rev Bras Reumatol. 2015;55:1–21. [ Links ]

Received: September 13, 2018; Accepted: October 16, 2018; Published: November 23, 2018

* Correspondence: clovisaasilva@gmail.com

Authors' contributions

All authors analyzed and interpreted the patient data regarding autoimmune hepatitis in childhood onset systemic lupus erythematosus. GB, EB and CAS were the major contributor in writing the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.