Skip to main content

Advertisement

SpringerLink
Log in

Predictors of damage accrual in systemic lupus erythematosus: a longitudinal observational study with focus on neuropsychological factors and anti-neuronal antibodies

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Central nervous system disease occurs in over 20% of patients with systemic lupus erythematosus (SLE) resulting in major morbidity and damage. Cognitive dysfunction is common in SLE, but the cause remains uncertain and treatment options are limited. This study explores the influence of clinical, neuropsychological factors and anti-neuronal antibodies on lupus damage accrual.

Method

A prospective cohort with 99 SLE patients recruited between 2008 and 2013 and followed up in 2016 was established. Baseline evaluations were depression (MINI-Plus), cognitive function evaluating attention, visuospatial memory and executive functions, and anti-neuronal antibodies. Activity index (SLEDAI-2K) and SLICC/ACR Damage Index (SDI) were assessed at baseline and last follow-up.

Results

At baseline, median (interquartile range) age was 36.0 years (27.0–45.0), disease duration 3.7 years (0.4–12.4), SLEDAI-2K 6.0 (3.0–12.0), and SDI score 1.0 (0–1.0). Major depression was present in 23%, cognitive deficit in 18%, and received immunomodulators in 36%. Anti-dsDNA/N-methyl-d-aspartate receptor antibodies were present in 19%, anti-ribosomal P in 12%, and anti-neuronal surface P antigen (NSPA) in 5%. After a median follow-up of 55 months (interquartile range 39–78), 11% had damage accrual. In a multivariate analysis, baseline SDI, SLEDAI-2K, and immunomodulators use were associated with final damage, whereas SLEDAI-2K and immunomodulator use were also associated with accrual damage. Models including anti-NSPA showed impact on final and accrual damage. Cognitive deficit, depression, and other autoantibodies were not predictors.

Conclusions

Disease activity and immunomodulator use associate with lupus damage. Of the anti-neuronal antibodies examined, anti-NSPA emerged as a potential poor prognostic factor, probably related to severe SLE onset requiring elevated corticosteroid doses.

Key Points

• Anti-NSPA may be a worse prognostic factor in SLE.

• Other neuropsychological factors do not influence damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G, Hughes G (2016) Systemic lupus erythematosus. Nat Rev Dis Primers 2:16039

    Article  PubMed  Google Scholar 

  2. Sutton EJ, Davidson JE, Bruce IN (2013) The systemic lupus international collaborating clinics (SLICC) damage index: a systematic literature review. Semin Arthritis Rheum 43:352–361

    Article  PubMed  Google Scholar 

  3. Yee CS, Su L, Toescu V, Hickman R, Situnayake D, Bowman S, Farewell V, Gordon C (2015) Birmingham SLE cohort: outcomes of a large inception cohort followed for up to 21 years. Rheumatology (Oxford) 54:836–843

    Article  CAS  Google Scholar 

  4. Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, Hanly JG, Isenberg DA, Kalunian K, Nived O, Petri M, Sanchez-Guerrero J, Snaith M, Sturfelt G (1997) The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum 40:809–813

    Article  CAS  PubMed  Google Scholar 

  5. Taraborelli M, Cavazzana I, Martinazzi N, Lazzaroni MG, Fredi M, Andreoli L, Franceschini F, Tincani A (2017) Organ damage accrual and distribution in systemic lupus erythematosus patients followed-up for more than 10 years. Lupus 26:1197–1204

    Article  CAS  PubMed  Google Scholar 

  6. Alarcon GS, McGwin G Jr, Bartolucci AA, Roseman J, Lisse J, Fessler BJ, Bastian HM, Friedman AW, Reveille JD, Lumina Study Group. Lupus in Minority Populations NvN (2001) Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual. Arthritis Rheum 44:2797–2806

    Article  CAS  PubMed  Google Scholar 

  7. Gladman DD, Urowitz MB, Rahman P, Ibanez D, Tam LS (2003) Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol 30:1955–1959

    PubMed  Google Scholar 

  8. Mok CC, Ho CT, Wong RW, Lau CS (2003) Damage accrual in southern Chinese patients with systemic lupus erythematosus. J Rheumatol 30:1513–1519

    PubMed  Google Scholar 

  9. Bruce IN, O’Keeffe AG, Farewell V, Hanly JG, Manzi S, Su L, Gladman DD, Bae SC, Sanchez-Guerrero J, Romero-Diaz J, Gordon C, Wallace DJ, Clarke AE, Bernatsky S, Ginzler EM, Isenberg DA, Rahman A, Merrill JT, Alarcón GS, Fessler BJ, Fortin PR, Petri M, Steinsson K, Dooley MA, Khamashta MA, Ramsey-Goldman R, Zoma AA, Sturfelt GK, Nived O, Aranow C, Mackay M, Ramos-Casals M, van Vollenhoven RF, Kalunian KC, Ruiz-Irastorza G, Lim S, Kamen DL, Peschken CA, Inanc M, Urowitz MB (2015) Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis 74:1706–1713

    Article  CAS  PubMed  Google Scholar 

  10. Fessler BJ, Alarcon GS, McGwin G Jr, Roseman J, Bastian HM, Friedman AW, Baethge BA, Vila L, Reveille JD, Group LS (2005) Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum 52:1473–1480

    Article  PubMed  Google Scholar 

  11. Borowoy AM, Pope JE, Silverman E, Fortin PR, Pineau C, Smith CD, Arbillaga H, Gladman D, Urowitz M, Zummer M, Hudson M, Tucker L, Peschken C (2012) Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 faces of lupus cohort. Semin Arthritis Rheum 42:179–185

    Article  PubMed  Google Scholar 

  12. Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-Romo D, Stallworth CL, Valdez CR, Escalante A, del Rincon I, Gronseth G, Rhine CB, Padilla P et al (2002) Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology 58:1214–1220

    Article  CAS  PubMed  Google Scholar 

  13. Hanly JG (2014) Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol 10:338–347

    Article  CAS  PubMed  Google Scholar 

  14. Tomietto P, Annese V, D’Agostini S, Venturini P, La Torre G, De Vita S, Ferraccioli GF (2007) General and specific factors associated with severity of cognitive impairment in systemic lupus erythematosus. Arthritis Rheum 57:1461–1472

    Article  CAS  PubMed  Google Scholar 

  15. Petri M, Naqibuddin M, Carson KA, Sampedro M, Wallace DJ, Weisman MH, Holliday SL, Padilla PA, Brey RL (2008) Cognitive function in a systemic lupus erythematosus inception cohort. J Rheumatol 35:1776–1781

    Article  PubMed  Google Scholar 

  16. Conti F, Alessandri C, Perricone C, Scrivo R, Rezai S, Ceccarelli F, Spinelli FR, Ortona E, Marianetti M, Mina C, Valesini G (2012) Neurocognitive dysfunction in systemic lupus erythematosus: association with antiphospholipid antibodies, disease activity and chronic damage. PLoS One 7:e33824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ceccarelli F, Perricone C, Pirone C, Massaro L, Alessandri C, Mina C, Marianetti M, Spinelli FR, Valesini G, Conti F (2018) Cognitive dysfunction improves in systemic lupus erythematosus: results of a 10 years prospective study. PLoS One 13:e0196103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Calderon J, Flores P, Babul M, Aguirre JM, Slachevsky A, Padilla O, Scoriels L, Henriquez C, Carcamo C, Bravo-Zehnder M, Gonzalez A, Massardo L (2014) Systemic lupus erythematosus impairs memory cognitive tests not affected by depression. Lupus 23:1042–1053

    Article  CAS  PubMed  Google Scholar 

  19. Massardo L, Bravo-Zehnder M, Calderon J, Flores P, Padilla O, Aguirre JM, Scoriels L, Gonzalez A (2015) Anti-N-methyl-D-aspartate receptor and anti-ribosomal-P autoantibodies contribute to cognitive dysfunction in systemic lupus erythematosus. Lupus 24:558–568

    Article  CAS  PubMed  Google Scholar 

  20. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT (2009) Losing your nerves? Maybe it’s the antibodies. Nat Rev Immunol 9:449–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tay SH, Fairhurst AM, Mak A (2017) Clinical utility of circulating anti-N-methyl-d-aspartate receptor subunits NR2A/B antibody for the diagnosis of neuropsychiatric syndromes in systemic lupus erythematosus and Sjogren’s syndrome: an updated meta-analysis. Autoimmun Rev 16:114–122

    Article  CAS  PubMed  Google Scholar 

  22. Gonzalez A, Massardo L (2018) Antibodies and the brain: antiribosomal P protein antibody and the clinical effects in patients with systemic lupus erythematosus. Curr Opin Neurol 31:300–305

    Article  CAS  PubMed  Google Scholar 

  23. Lakhan SE, Caro M, Hadzimichalis N (2013) NMDA receptor activity in neuropsychiatric disorders. Front Psychiatry 4:52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bonfa E, Golombek SJ, Kaufman LD, Skelly S, Weissbach H, Brot N, Elkon KB (1987) Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 317:265–271

    Article  CAS  PubMed  Google Scholar 

  25. Matus S, Burgos PV, Bravo-Zehnder M, Kraft R, Porras OH, Farias P, Barros LF, Torrealba F, Massardo L, Jacobelli S, Gonzalez A (2007) Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. J Exp Med 204:3221–3234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Segovia-Miranda F, Serrano F, Dyrda A, Ampuero E, Retamal C, Bravo-Zehnder M, Parodi J, Zamorano P, Valenzuela D, Massardo L, van Zundert B, Inestrosa NC, González A (2015) Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model. Arthritis Rheumatol 67:1598–1610

    Article  CAS  PubMed  Google Scholar 

  27. Bravo-Zehnder M, Toledo EM, Segovia-Miranda F, Serrano FG, Benito MJ, Metz C, Retamal C, Alvarez A, Massardo L, Inestrosa NC, Gonzalez A (2015) Anti-ribosomal P protein autoantibodies from patients with neuropsychiatric lupus impair memory in mice. Arthritis Rheumatol 67:204–214

    Article  CAS  PubMed  Google Scholar 

  28. Calderon J, Flores P, Aguirre JM, Valdivia G, Padilla O, Barra I, Scoriels L, Herrera S, Gonzalez A, Massardo L (2017) Impact of cognitive impairment, depression, disease activity, and disease damage on quality of life in women with systemic lupus erythematosus. Scand J Rheumatol 46:273–280

    Article  CAS  PubMed  Google Scholar 

  29. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

    Article  CAS  PubMed  Google Scholar 

  30. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI (1990) Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 113:941–948

    Article  CAS  PubMed  Google Scholar 

  31. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR (2006) The Addenbrooke’s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 21:1078–1085

    Article  PubMed  Google Scholar 

  32. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 35:630–640

    Article  CAS  PubMed  Google Scholar 

  33. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, Groot PGDE, Koike T, Meroni PL, Reber G, Shoenfeld Y et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306

    Article  CAS  PubMed  Google Scholar 

  34. (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42:599–608

  35. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370

    Article  CAS  PubMed  Google Scholar 

  36. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33 quiz 4-57

    PubMed  Google Scholar 

  37. Association AP (2004) Diagnostic and statistical manual of mental disorders-IV, 4th edn. Washington

  38. Robbins TW, James M, Owen AM, Sahakian BJ, McInnes L, Rabbitt P (1994) Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5:266–281

    CAS  PubMed  Google Scholar 

  39. Ad Hoc Committee on Lupus Response Criteria: Cognition S-c, Mikdashi JA, Esdaile JM, Alarcon GS, Crofford L, Fessler BJ, Shanberg L, Brunner H, Gall V, Kalden JR, Lockshin MD, Liang MH et al (2007) Proposed response criteria for neurocognitive impairment in systemic lupus erythematosus clinical trials. Lupus 16:418–425

    Article  Google Scholar 

  40. Yazdany J, Yelin EH, Panopalis P, Trupin L, Julian L, Katz PP (2008) Validation of the systemic lupus erythematosus activity questionnaire in a large observational cohort. Arthritis Rheum 59:136–143

    Article  PubMed  PubMed Central  Google Scholar 

  41. Petri M, Purvey S, Fang H, Magder LS (2012) Predictors of organ damage in systemic lupus erythematosus: the Hopkins Lupus Cohort. Arthritis Rheum 64:4021–4028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Keeling SO, Vandermeer B, Medina J, Chatterley T, Nevskaya T, Pope J, Alaburubalnabi Z, Bissonauth A, Touma Z (2018) Measuring disease activity and damage with validated metrics: a systematic review on mortality and damage in systemic lupus erythematosus. J Rheumatol 45:1448–1461

    Article  PubMed  Google Scholar 

  43. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA (2012) Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford) 51:491–498

    Article  Google Scholar 

  44. Nery FG, Borba EF, Hatch JP, Soares JC, Bonfa E, Neto FL (2007) Major depressive disorder and disease activity in systemic lupus erythematosus. Compr Psychiatry 48:14–19

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients who participated in this study, Teresa Cole for the English version of the manuscript. We are indebted to Dr. Betty Diamond for performing the anti-dsDNA/NMDAR antibodies.

Funding

This work received financial support from Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant no. 1160513 to LM, and from Programa de Apoyo a Centros con Financiamiento Basal AFB 170005 and AFB 170004 from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) to AG.

Author information

Authors and Affiliations

  1. Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Carmen Sylva 2444, Providencia, 7510156, Santiago, Chile

    Milena Mimica, Marcela Bravo-Zehnder, Alfonso González & Loreto Massardo

  2. Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Ignacio Barra

  3. Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Rocío Ormeño

  4. Departamento de Psiquiatría, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Patricia Flores & Jorge Calderón

  5. Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Oslando Padilla

  6. Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    Alfonso González

  7. Fundación Ciencia y Vida, Santiago, Chile

    Alfonso González

Authors
  1. Milena Mimica
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ignacio Barra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rocío Ormeño
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patricia Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jorge Calderón
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Oslando Padilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcela Bravo-Zehnder
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alfonso González
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Loreto Massardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Loreto Massardo.

Ethics declarations

Disclosures

None.

Ethical statement

All participants voluntarily signed an informed consent approved by the Pontificia Universidad Católica de Chile Ethical Committee prior to their inclusion in the study, in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(DOCX 68 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mimica, M., Barra, I., Ormeño, R. et al. Predictors of damage accrual in systemic lupus erythematosus: a longitudinal observational study with focus on neuropsychological factors and anti-neuronal antibodies. Clin Rheumatol 38, 3129–3137 (2019). https://doi.org/10.1007/s10067-019-04707-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04707-x

Keywords

Indexing terms

Search

Navigation