Lupus (2017) 26, 484–489 journals.sagepub.com/home/lup SPECIAL ARTICLE Anti-ribosomal P antibody: a multicenter study in childhood-onset systemic lupus erythematosus patients CCM Valões1, BC Molinari1, ACG Pitta1, NWS Gormezano1,2, SCL Farhat1, K Kozu1, AME Sallum1, S Appenzeller3, AP Sakamoto4, MT Terreri4, RMR Pereira2, CS Magalhães5, JCOA Ferreira1, CM Barbosa6, FH Gomes7, E Bonfá2 and CA Silva1,2, Brazilian Childhood-onset Systemic Lupus Erythematosus Group 1Pediatric Rheumatology Unit, Children’s Institute, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brazil; 2Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brazil; 3Pediatric Rheumatology Unit, State University of Campinas (UNICAMP), Brazil; 4Pediatric Rheumatology Unit, Universidade Federal de São Paulo (UNIFESP), Brazil; 5Pediatric Rheumatology Division, São Paulo State University (UNESP) – Faculdade de Medicina de Botucatu, Brazil; 6Pediatric Rheumatology Unit, Hospital Darcy Vargas, Brazil; and 7Pediatric Rheumatology Unit, Ribeirão Preto Medical School – FMUSP, Brazil Objectives: Anti-ribosomal P protein (anti-P) autoantibodies are highly specific for systemic lupus erythematosus (SLE). However, the evaluation of this autoantibody in childhood-onset SLE (cSLE) populations has been limited to a few small series, hampering the interpretation of the clinical and laboratorial associations. Therefore, the objective of this multicenter cohort study was to evaluate demographic, clinical/laboratorial features, and disease damage score in cSLE patients with and without the presence of anti-P antibody. Methods: This was a retro- spective multicenter study performed in 10 pediatric rheumatology services of São Paulo state, Brazil. Anti-P antibodies were measured by ELISA in 228 cSLE patients. Results: Anti-P antibodies were observed in 61/228 (27%) cSLE patients. Frequencies of cumulative lymph- adenopathy (29% vs. 15%, p¼ 0.014), acute confusional state (13% vs. 5%, p¼ 0.041), mood disorder (18% vs. 8%, p¼ 0.041), autoimmune hemolytic anemia (34% vs. 15%, p¼ 0.001), as well as presence of anti-Sm (67% vs. 40%, p¼ 0.001), anti-RNP (39% vs. 21%, p¼ 0.012) and anti-Ro/SSA antibodies (43% vs. 25%, p¼ 0.016) were significantly higher in cSLE patients with anti-P antibodies compared to those without these autoantibodies. A multiple regression model revealed that anti-P antibodies were associated with autoimmune hemolytic anemia (odds ratio (OR)¼ 2.758, 95% confidence interval (CI): 1.304–5.833, p¼ 0.008) and anti-Sm antibody (OR¼ 2.719, 95% CI: 1.365–5.418, p¼ 0.004). The SLICC/ACR damage index was comparable in patients with and without anti-P antibodies (p¼ 0.780). Conclusions: The novel association of anti-P antibodies and autoimmune hemolytic anemia was evidenced in cSLE patients and further studies are necessary to determine if anti-P titers may vary with this hematological manifestation. Lupus (2017) 26, 484–489. Key words: Systemic lupus erythematosus; anti- ribosomal P protein antibodies; neuropsychi- atric lupus; autoimmune hemolytic anemia; childhood Introduction Anti-ribosomal P protein (anti-P) autoantibodies recognize three ribosomal phosphoproteins, called P0, P1, and P2.1 These autoantibodies are highly specific for systemic lupus erythematosus (SLE).2,3 Clinical associations reported were disease activity, neuropsychiatric,4,5 and renal involvements.3–5 The prevalence of anti-P in childhood-onset SLE (cSLE) populations varies from4,6-9 20% to10 42%, a frequency higher than described in adult-onset SLE (aSLE) patients.3,8–10 However, the evaluation of this autoantibody in cSLE populations has been limited to a few small series,4,6–10 hampering the interpret- ation of the clinical and laboratorial associations. Therefore, the objective of this multicenter cohort study was to evaluate demographic, cumu- lative clinical/laboratorial features, and disease damage score in cSLE patients with and without the presence of anti-P antibody. Correspondence to: Clovis Artur Silva, Av. Dr. Eneas Carvalho Aguiar, 647 – Cerqueira César São Paulo – SP, 05403-000 Brazil. Email: clovisaasilva@gmail.com ! The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203316676386 http://crossmark.crossref.org/dialog/?doi=10.1177%2F0961203316676386&domain=pdf&date_stamp=2017-04-10 Methods Study design and patients This was a retrospective multicenter study per- formed in 10 pediatric rheumatology services of São Paulo state, Brazil, and included 228 cSLE patients that underwent anti-P antibody evalu- ation. All patients fulfilled the American College of Rheumatology (ACR) criteria,11 with disease onset before 18 years of age.12 An investigator meeting in São Paulo defined the protocol for this study that included clinical and laboratory parameters, as previously described.13–18 Neuropsychiatric lupus, which includes 19 syndromes according to ACR classifi- cation criteria, can be subdivided into peripheral and central nervous system involvement.19 Antiphospholipid syndrome was diagnosed accord- ing to the preliminary criteria for the classification of pediatric antiphospholipid syndrome.20 High blood pressure was defined as systolic and/or dia- stolic blood pressures �95th percentile for gender, age, and height on �3 occasions.21 Acute kidney injury was determined by sudden increase in serum creatinine above 2mg/dL or by modified RIFLE (risk, injury, failure, loss of kidney func- tion, and end-stage kidney disease) criteria.22 Chronic renal disease was defined as structural or function abnormalities of the kidney for �3 months (with or without decreased glomerular filtration rate) or glomerular filtration rate <60mL/min/ 1.73 m2 for �3 months.23 The anti-P antibody was measured by ELISA, antinuclear antibodies (ANA) tested by indirect immunofluorescence, anti-dsDNA by indirect immunofluorescence or ELISA, anti-Sm and anti- RNP by passive hemagglutination or ELISA, anti- SSA/Ro and anti-SSB/La by counterimmunoelec- trophoresis or ELISA, and anticardiolipin (aCL) IgG and IgM by ELISA, carried out at each center. The cutoff values were defined according to kit manufacturer. Lupus anticoagulant (LA) was detected according to the guidelines of the International Society on Thrombosis and Hemostasis.24 At last visit, the Systemic Lupus International Collaborating Clinics/ACR damage index (SLICC-ACR/DI) was evaluated.25 Statistical analysis Descriptive statistics are presented as an absolute number (frequency) for categorical variables and median (minimum and maximum values) for con- tinuous variables. Categorical variables were assessed by Pearson’s chi-squared test or by Fisher test. Continuous variables were analyzed according to Mann–Whitney test. Logistic regres- sion models were performed to identify independ- ent variables associated with the presence of anti-P antibodies. In the multiple model, we used as inde- pendent variables those that presented a level 20% of significance in the univariate analysis. Results of the regression model are shown as the odds ratio (OR) and 95% confidence interval (95% CI). We adopted a significance level of 5% in all analyses. Results Anti-P antibody was evidenced in 61/228 (27%). Demographic data, cumulative clinical manifest- ations, and disease damage score at last visit in c-SLE patients according to presence of anti-P autoantibody are shown in Table 1. Frequencies of cumulative lymphadenopathy (29% vs. 15%, p¼ 0.014), acute confusional state (13% vs. 5%, p¼ 0.041), mood disorder (18% vs. 8%, p¼ 0.041), and autoimmune hemolytic anemia (34% vs. 15%, p¼ 0.001) were significantly higher in cSLE patients with anti-P antibodies compared to those without these autoantibodies. The median SLICC/ACR-DI scores were comparable in patients with and without anti-P antibodies (p> 0.05, Table 1). Frequencies of anti-Sm (67% vs. 40%, p¼ 0.001), anti-RNP (39% vs. 21%, p¼ 0.012), and anti-Ro/SSA antibodies (43% vs. 25%, p¼ 0.016) were significantly higher in cSLE patients with the presence of anti-P antibodies compared to those without these autoantibodies (Table 2). A multiple regression model revealed that anti-P antibody was associated with autoimmune hemo- lytic anemia (OR¼ 2.758, 95% CI: 1.304–5.833, p¼ 0.008) and anti-Sm antibody (OR¼ 2.719, 95% CI: 1.365–5.418, p¼ 0.004) (Table 3). Discussion A novel association of anti-P antibodies and auto- immune hemolytic anemia was identified in cSLE patients. We also confirmed the association of anti- P and anti-Sm antibodies. The advantages of the present study were as fol- lows: the multicenter study included a large cSLE population; the assessment of 19 standardized neuropsychiatric syndromes was according to ACR classification criteria;19 and evaluation of Anti-P in cSLE patients CCM Valões et al. 485 Lupus Table 1 Demographic data, cumulative clinical manifestations, and disease damage score at last visit in 228 cSLE patients according to presence of anti-P autoantibody Variables Anti-P positive (n¼ 61) Anti-P negative (n¼ 167) p Demographic data Age at last visit, years, n¼ 228 18 (2–25) 17.8 (2–25.3) 0.230 Disease duration, years, n¼ 228 5 (0.1–23) 6 (0.1–22) 0.447 Female gender, n¼ 228 54/61 (88) 145/167 (87) 0.733 Constitutional manifestations, n¼ 228 39/61 (64) 99/167(59) 0.525 Fever, n¼ 227 35/61 (57) 94/166 (57) 0.919 Reticuloendothelial manifestations, n¼ 228 24/61 (39) 44/167 (26) 0.058 Lymphadenopathy, n¼ 227 18/61 (29) 25/166 (15) 0.014 Hepatomegaly, n¼ 228 13/61 (21) 28/167 (17) 0.429 Splenomegaly, n¼ 227 7/61 (11) 12/166 (7) 0.306 Mucocutaneous involvement, n¼ 228 58/61 (95) 155/167 (93) 0.764 Rash, n¼ 228 46/61 (75) 125/167 (75) 0.931 Discoid lupus, n¼ 228 10/61 (16) 22/167 (13) 0.536 Photosensitivity, n¼ 228 44/61 (72) 116/167 (69) 0.696 Mucosal ulceration, n¼ 227 30/61(49) 65/166 (39) 0.175 Alopecia, n¼ 227 32/61 (52) 77/166 (46) 0.417 Vasculitis, n¼ 227 25/61 (41) 47/166 (28) 0.069 Musculoskeletal involvement, n¼ 228 50/61 (82) 139/167 (83) 0.822 Arthritis, n¼ 228 49/61 (80) 138/167 (83) 0.688 Myositis, n¼ 227 5/61 (8) 13/166(8) 1.000 Serositis, n¼ 227 26/61 (43) 53/166 (32) 0.134 Pleuritis, n¼ 227 18/61 (29) 32/166 (19) 0.099 Pericarditis, n¼ 227 15/61 (25) 40/166 (24) 0.939 Nephritis, n¼ 228 29/61 (47) 81/167 (48) 0.898 Arterial hypertension, n¼ 226 19/61 (31) 51/165 (31) 0.973 Acute renal failure, n¼ 227 12/61 (20) 22/166 (13) 0.230 Chronic renal failure, n¼ 227 3/61 (5) 8/166 (5) 0.975 Renal replacement therapy, n¼ 193 5/50 (10) 6/143 (4) 0.157 Neuropsychiatric involvement, n¼ 228 30/61(49) 90/167(54) 0.528 Central nervous system, n¼ 228 29/61 (47) 89/167 (53) 0.442 Acute confusional state, n¼ 227 8/61 (13) 8/166 (5) 0.041 Aseptic meningitis, n¼ 227 0/61 (0) 2/166 (1) 1.000 Cerebrovascular disease, n¼ 225 2/61 (3) 1/164(1) 0.179 Demyelinating syndrome, n¼ 227 0/61 (0) 0/166 (0) – Headache, n¼ 227 19/61 (31) 58/166 (35) 0.593 Movement disorder chorea, n¼ 227 2/61 (3) 4/166 (2) 0.661 Myelopathy, n¼ 227 0/61 (0) 3/166 (2) 0.566 Seizure disorders, n¼ 228 8/61 (13) 30/167(18) 0.384 Anxiety disorder, n¼ 227 4/61 (7) 5/166 (3) 0.255 Cognitive dysfunction, n¼ 227 2/61 (3) 8/166 (5) 0.055 Mood disorder, n¼ 227 11/61 (18) 14/166 (8) 0.041 Psychosis, n¼ 226 9/61 (15) 19/165 (12) 0.512 Peripheral nervous system, n¼ 227 3/61(5) 9/166 (5) 1.000 Guillain–Barré syndrome, n¼ 228 0/61(0) 0/167(0) – Autonomic disorder, n¼ 226 1/61(2) 0/165(0) 0.270 Mononeuropathy, single/multiplex, n¼ 228 2/61(3) 3/167(2) 0.614 Myasthenia gravis, n¼ 225 0/61 (0) 0/164(0) – Neuropathy, cranial, n¼ 228 0/61 (0) 1/167(1) 1.000 Plexopathy, n¼ 226 0/61 (0) 0/165(0) – Polyneuropathy, n¼ 226 0/61(0) 5/165(3) 0.327 Visual disturbance, n¼ 227 0/61 (0) 3/166 (2) 0.566 Autoimmune thrombosis (APS), n¼ 222 2/59 (3) 15/163 (9) 0.251 Disease damage score SLICC/ACR-DI at last visit n¼ 213 0 (0–7) 0 (0–6) 0.780 Results are presented as n (%) or median (range); APS – antiphospholipid syndrome; SLICC/ACR-DI – Systemic Lupus International Collaborating Clinics/ACR damage index. Anti-P in cSLE patients CCM Valões et al. 486 Lupus these autoantibodies was by a method commonly used in clinical practice with high sensitivity and specificity.3 A limitation of the present report is the fact that it was a retrospective study with miss- ing data. The frequency of anti-P autoantibodies in cSLE patients observed in the present study was similar to that reported for pediatric SLE populations.4,7–9,26–30 An original and important finding of this study was the association with autoimmune hemolytic anemia, suggesting that the anti-P may target erythrocytes. Possible underlying mechanisms include apoptosis, cross-reactivity, and enhanced proinflammatory cytokine production induced by this antibody.3 However, the clinical relevance of this hematological finding must be confirmed in prospective studies. Proposed explanations for multiple autoanti- body production observed in our cSLE patients may be due to random polyclonal B cell activation, widespread abnormal expansion of a B cell subset and an antigen-driven immune response. Association between anti-P and anti Sm autoanti- bodies were also previously reported in both human SLE and in mice.5,27 The higher frequency of mood disorders and acute confusional state in anti-P positive patients in the univariate analysis did not remain in multi- variate assessment. Anti-P antibody activity fluctu- ation may account for this discrepancy since the retrospective evaluation of cumulative neuro- psychiatric involvement performed herein may hamper the interpretation of attribution for psychi- atric and cognitive dysfunction.29 Indeed, a more appropriate study design indicates that anti-P in cSLE patients is associated with psychosis,27 anx- iety disorders,4 and cognitive impairment.29 In conclusion, the novel association of anti-P antibodies and autoimmune hemolytic anemia was evidenced in cSLE patients and further studies are necessary to determine if anti-P titers may vary with this hematological manifestation. Acknowledgments The authors wish to thank Ulysses Doria-Filho for the statistical analysis. Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Table 3 Independent variables in the multiple regression models associated with anti-P autoantibody in 228 cSLE patients Independent variables OR (95% CI) p Autoimmune hemolytic anemia, n¼ 226 2.758 (1.304–5.833) 0.008 Anti-Sm autoantibodies, n¼ 189 2.719 (1.365–5.418) 0.004 OR – odds ratio; 95% CI – 95% confidence interval. Table 2 Cumulative hematological abnormalities, laboratory results, and treatments at last visit in 228 cSLE patients according to presence of anti-P autoantibody Variables Anti-P positive (n¼ 61) Anti-P negative (n¼ 167) p Cumulative hematological abnormalities Autoimmune hemolytic anemia, n¼ 226 21/61 (34) 25/165 (15) 0.001 Leukopenia< 4000/mm3, n¼ 227 21/61 (34) 53/166 (32) 0.722 Lymphopenia< 1500/mm3, n¼ 226 35/60 (58) 81/166 (49) 0.205 Thrombocytopenia< 100,000/mm3, n¼ 227 10/61 (16) 37/166 (22) 0.331 Cumulative autoantibodies ANA, n¼ 225 61/61 (100) 163/164 (99) 1.000 Anti-dsDNA, n¼ 227 43/61 (70) 112/166 (67) 0.665 Anti-Sm, n¼ 189 34/51 (67) 55/138 (40) 0.001 Anti-RNP, n¼ 180 20/51 (39) 27/129 (21) 0.012 Anti SSA/Ro, n¼ 183 22/51 (43) 33/132 (25) 0.016 Anti SSB/La, n¼ 183 11/51 (22) 21/132 (16) 0.366 LA, n¼ 137 3/37 (8) 17/100 (17) 0.191 aCL IgM, n¼ 150 4/42 (9) 22/108 (20) 0.115 aCL IgG, n¼ 150 5/44 (11) 23/106 (22) 0.139 Results are presented as n (%). Anti-P in cSLE patients CCM Valões et al. 487 Lupus Funding The author(s) disclosed receipt of the following finan- cial support for the research, authorship, and/or pub- lication of this article: this work was supported by Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq; grant numbers 301805/2013-0, 303752/2015-7, 301479/2015-1, 305068/2014-8, and 303422/2015-7), the Federico Foundation, and by Núcleo de Apoio à Pesquisa ‘‘Saúde da Criança e do Adolescente’’ da USP (NAP-CriAd). Notes The collaborators of the Brazilian Childhood-onset Systemic Lupus Erythematosus Group are as follows: 1. Marco F. Silva, Children’s Institute, FMUSP, São Paulo, Brazil 2. Mariana Ferriani, Children’s Institute, FMUSP, São Paulo, Brazil 3. Roberta C. Gomes, Children’s Institute, FMUSP, São Paulo, Brazil 4. Victor L. Marques, Children’s Institute, FMUSP, São Paulo, Brazil 5. Gabriela Blay, Children’s Institute, FMUSP, São Paulo, Brazil 6. Gabriella E. Lube, Children’s Institute, FMUSP, São Paulo, Brazil 7. Sandra R. M. Lopes, Children’s Institute, FMUSP, São Paulo, Brazil 8. João D. Montoni, Children’s Institute, FMUSP, São Paulo, Brazil 9. Laila P. Coelho, Children’s Institute, FMUSP, São Paulo, Brazil 10. Luciana S. Henriques, Children’s Institute, FMUSP, São Paulo, Brazil 11. Glaucia V. Novak, Children’s Institute, FMUSP, São Paulo, Brazil 12. Juliana B. Brunelli, Children’s Institute, FMUSP, São Paulo, Brazil 13. Lucia M. A. Campos, Children’s Institute, FMUSP, São Paulo, Brazil 14. Nadia E. Aikawa, Children’s Institute, FMUSP, São Paulo, Brazil 15. Adriana A. Jesus, Children’s Institute, FMUSP, São Paulo, Brazil 16. Antonio C. Pastorino, Children’s Institute, FMUSP, São Paulo, Brazil 17. Heloisa H. Marques, Children’s Institute, FMUSP, São Paulo, Brazil 18. Joaquim C. Rodrigues, Children’s Institute, FMUSP, São Paulo, Brazil 19. Andrea Watanabe, Children’s Institute, FMUSP, São Paulo, Brazil 20. Benita G. Schvartsman, Children’s Institute, FMUSP, São Paulo, Brazil 21. Maria H. Vaisbich, Children’s Institute, FMUSP, São Paulo, Brazil 22. Werther B. Carvalho, Children’s Institute, FMUSP, São Paulo, Brazil 23. Magda Carneiro-Sampaio, Children’s Institute, FMUSP, São Paulo, Brazil 24. Vicente Odone-Filho, Children’s Institute, FMUSP, São Paulo, Brazil 25. Juliane A. Paupitz, Division of Rheumatology, FMUSP, São Paulo, Brazil 26. Glauce L. Lima, Division of Rheumatology, FMUSP, São Paulo, Brazil 27. Ana Paula L. Assad, Division of Rheumatology, FMUSP, São Paulo, Brazil 28. Claudio Len, UNIFESP, São Paulo, Brazil 29. Maria O. E. Hilário, UNIFESP, São Paulo, Brazil 30. Andreia S. Lopes, UNIFESP, São Paulo, Brazil 31. Aline Alencar, UNIFESP, São Paulo, Brazil 32. Daniela P. Piotto, UNIFESP, São Paulo, Brazil 33. Giampaolo Faquin, UNIFESP, São Paulo, Brazil 34. Gleice Clemente, UNIFESP, São Paulo, Brazil 35. Octavio A. B. Peracchi, UNIFESP, São Paulo, Brazil 36. Vanessa Bugni, UNIFESP, São Paulo, Brazil 37. Priscila R. Aoki, UNESP, São Paulo, Brazil 38. Juliana O. Sato, UNESP, São Paulo, Brazil 39. Silvana P. Cardin, UNESP, São Paulo, Brazil 40. Taciana A. P. Fernandes, UNESP, São Paulo, Brazil; 41. Andressa Guariento, Irmandade da Santa Casa de Misericórdia de São Paulo, Brazil 42. Eunice Okuda, Irmandade da Santa Casa de Misericórdia de São Paulo, Brazil 43. Maria Carolina dos Santos, Irmandade da Santa Casa de Misericórdia de São Paulo, Brazil 44. Silvana B. Sacchetti, Irmandade da Santa Casa de Misericórdia de São Paulo, Brazil 45. Maraı́sa Centeville, UNICAMP, São Paulo, Brazil 46. Renata Barbosa, UNICAMP, São Paulo, Brazil 47. Roberto Marini, UNICAMP, São Paulo, Brazil; 48. Paola P. Kahwage, Ribeirão Preto Medical School, FMUSP, São Paulo, Brazil 49. Gecilmara Pileggi, Ribeirão Preto Medical School, FMUSP, São Paulo, Brazil 50. Luciana M. Carvalho, Ribeirão Preto Medical School, FMUSP, São Paulo, Brazil 51. Virginia Ferriani, Ribeirão Preto Medical School, FMUSP, São Paulo, Brazil 52. Jonatas Libório, Hospital Infantil Darcy Vargas, São Paulo, Brazil 53. Luciana T. P. Paulo, Hospital Infantil Darcy Vargas, São Paulo, Brazil 54. Simone Lotufo, Hospital Municipal Infantil Menino Jesus, São Paulo, Brazil 55. Tânia Caroline M. Castro, Hospital Municipal Infantil Menino Jesus, São Paulo, Brazil 56. Valéria C. Ramos, Pontifical Catholic University of Sorocaba, São Paulo, Brazil 57. Luis Eduardo C. Andrade, UNIFESP, São Paulo, Brazil Anti-P in cSLE patients CCM Valões et al. 488 Lupus References 1 Bonfa E, Golombek SJ, Kaufman LD, et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 1987; 317: 265–6. 2 Sciascia S, Bertolaccini ML, Roccatello D, et al. Autoantibodies involved in neuropsychiatric manifestations associated with sys- temic lupus erythematosus: a systematic review. J Neurol 2014; 261: 1706–1714. 3 Pasoto SG, Viana VS, Bonfa E. 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