JEAN-LUC SENÉCAL, MD, FRCPC, FACP,
Professor of Medicine,
Department of Medicine, Division of Rheumatology,
University of Montreal Faculty of Medicine;
YVES RAYMOND, PhD,
Professor of Medicine,
Department of Medicine, Division of Rheumatology,
University of Montreal Faculty of Medicine,
Montreal, Quebec, Canada
Supported in part by grant MOP-62687 from the Canadian Institutes of Health Research.
Address reprint requests to Dr. J-L. Senécal, Autoimmunity Research Laboratory, Division of Rheumatic Diseases, M-4215, Hôpital Notre-Dame, CHUM, 1560 East Sherbrooke Street, Montreal, Quebec H2L 4M1, Canada. E-mail: jl.senecal@sympatico.ca

Current concepts suggest several mechanisms contribute to the immunopathogenesis of neuropsychiatric manifestations in SLE (NP-SLE), including antiphospholipid (aPL) antibody-mediated ischemia, microthrombosis and noninflammatory vasculopathy^1,2, local production of cytokines leading to neuronal cytotoxicity^3-5, and direct interaction of autoantibodies (aAb) with autoantigens (aAg) on neuronal cell membranes, leading to interference with neurotransmission, loss of neuronal plasticity, and neuronal cell death⁶. In this brief review, we discuss NP-SLE nomenclature and provide an opinion on how strongly current evidence does indeed support the concept of aAb-mediated neural cell injury in NP-SLE, with emphasis on the central nervous system (CNS).

HISTORICAL BACKGROUND

Over 35 years ago, Johnson and Richardson, in their seminal description of neuropathological findings in SLE, noted at autopsy a high prevalence of brain microinfarcts and concluded that "SLE of the nervous system is, in most cases, a vascular disease involving very small vessels"⁷. However, they also noted that this vascular involvement was strikingly associated histopathologically with the "lack of any true arteritis," raising the question of what might cause these lesions. Ten years later, Mary Betty Stevens and colleagues reported on the remarkable diversity of NP-SLE manifestations, encompassing psychosis, seizures, strokes, cranial nerve abnormalities, chorea, meningitis, myelitis, and peripheral neuropathies⁸. Since then, many groups have expanded these observations. In the past 5 years alone, hundreds of reports have been published on NP-SLE, demonstrating not only the widespread scientific interest for these manifestations and their complexity, but also the elusive nature of their pathogenic causes (for reviews^1,9).

Virtually all parts of the central, peripheral, and autonomous nervous systems can be involved in SLE¹. The prevalence of CNS disease varies widely, from 15% to 75%. Such involvements are a major cause of reduction in quality of life, increased cumulative organ damage, and increased mortality. Some types of NP-SLE are uncommon (e.g., chorea), whereas others are common but often subtle (e.g., cognitive disorders). In many cases, the differential diagnosis is broad, including infection, side effects of medication, and metabolic abnormalities (e.g., uremia), making it a challenge for clinicians to diagnose and treat NP-SLE. These issues are compounded by the lack of universal diagnostic standards for NP-SLE disease. Also, application of sophisticated brain imaging and cognitive testing frequently reveals subclinical deficits whose clinical significance is unclear¹⁰.

NEW NP-SLE NOMENCLATURE AS A TOOL FOR IMPROVED STUDIES

A timely initiative was the publication in 1999, under the auspices of the American College of Rheumatology (ACR), of a standard nomenclature and set of case definitions for NP-SLE, providing a uniform methodology for defining clinical subsets of NP-SLE¹¹. Although designed primarily to facilitate and enhance clinical research, particularly multicenter studies, and not as a substitute for a clinical diagnosis, these concise diagnostic criteria and the broad differential diagnosis of the 19 NP-SLE syndromes are required reading for clinicians providing care to SLE patients. The complete case definitions are available on the Internet at: www.rheumatology.org/publications/ar/1999/ aprilappendix.asp?aud=mem.

In this issue of The Journal, Hanly and colleagues use the ACR nomenclature and case definitions to determine the prevalence and attribution of NP disease in an unselected cohort of 111 Canadian patients with SLE from a single center¹². During a mean disease duration of 10 years, 74 NP events occurred in 41 (37%) patients. These events were attributed to SLE itself, to non-SLE causes, or to both in 47%, 41%, and 12% of cases, respectively. Most events attributed to non-SLE causes consisted of migraine, tension headache, and mood disorders. Thus the criteria as they currently stand predictably picked up several non-SLE NP manifestations. In fact, the nomenclature has been criticized for some lack of specificity and inclusion of findings without objective abnormalities, such as headache, and revised criteria have been proposed^13,14.

Nevertheless, several conclusions stem from the study by Hanly, et al and the few other reports based on ACR nomenclature^12,15. First, discriminating accurately between NP manifestations truly attributable to SLE versus non-SLE causes is of paramount importance to achieve nosologically homogenous patient subsets, a prerequisite for studies focused on pathogenesis^12,14,15. The ACR nomenclature and case definitions, although not perfect, are an important step in that process. Second, multicenter studies collectively using the ACR nomenclature will be needed to achieve a sufficiently large sample size for etiological study of the rarer NP-SLE manifestations. Third, the great diversity of NP-SLE manifestations noted by Stevens⁸ and highlighted by the ACR nomenclature again raises the fundamental question of the pathogenesis of nervous system involvement in SLE. Moreover, although SLE is the prototypical systemic autoimmune disease associated with multiple aAb, the ACR nomenclature and diagnostic criteria for NP-SLE conspicuously exclude any aAb diagnostic test in the serum or cerebrospinal fluid (CSF)¹¹.

BY WHAT MECHANISMS ARE AUTOANTIBODIES TO INTRACELLULAR AUTOANTIGENS PATHOGENIC IN SLE?

To understand the immune mechanisms that may lead to CNS dysfunction, it is useful to review briefly the major pathogenic mechanisms of aAb to intracellular autoantigens in other organ systems. SLE is characterized by the presence of multiple aAb, several of which contribute to the pathogenesis of specific manifestations and are used as diagnostic criteria. Hence, elevated serum levels of aAb to nuclear autoantigens (ANA) are present in almost all SLE patients, and high levels of ANA such as anti-dsDNA, anti-Sm, or anti-nuclear lamin B1 are rarely seen in any other disease^16-18. Moreover, extensive studies over the past decades have yielded major insights on the mechanisms whereby certain ANA may contribute to SLE pathogenesis, as summarized in Table 1^18-24.

Table 1. Major pathogenic mechanisms involving human autoantibodies to intracellular autoantigens in SLE.

Interestingly, although the presence of antineuronal aAb has been known in SLE for over 2 decades²⁵ and several aAb potentially associated with NP-SLE have now been identified, optimal study of their pathogenicity has lagged behind those of ANA because of the great complexity of the nervous systems and the limited availability of nervous tissues²⁶. Therefore it is logical to apply to aAb associated with NP-SLE the mechanistic framework learned from the study of ANA (Table 1) in order to formulate some a priori guidelines for evaluation of pathogenicity: (1) SLE aAb directed to intracellular aAg may exert pathogenic effects by binding to extracellularly expressed cognate aAg or to cross-reactive epitopes. Therefore, strict neural tissue specificity may not be expected from all pathogenic aAb in NP-SLE. (2) As seen for nephritogenic anti-dsDNA (Table 1), a given aAb specificity is not necessarily restricted to a single pathogenic mechanism. (3) From the highly diverse NP-SLE manifestations, which correspond to involvement of distinct neural tissues, it can be predicted that no single aAb would account for all forms of injury, i.e., distinct aAb with different CNS targets would be expected. (4) Although the hallmark of the blood-brain barrier is its impermeability, therefore blocking access of serum autoantibodies to the CNS, its disruption by SLE disease processes and other permeating events could allow inflow of activated B cells, T cells, monocytes/macrophages, and potentially pathogenic serum autoantibodies into the CNS. Furthermore, activated lymphocytes can also cross the intact blood-brain barrier^26a. Also, in situ autoantibody synthesis from B cells within the CNS may also ocur de novo¹. (5) In contrast with anti-dsDNA aAb, immune-complex–mediated inflammation is not the central mechanism for CNS lupus²⁷. With few exceptions, autopsy studies usually demonstrate no evidence of vasculitis and little inflammation in sites of injury⁷. Therefore other pathogenic mechanisms, such as outlined in Table 1, are likely involved. (6) The identification of neural tissue-specific aAb cannot be construed as necessarily indicative of pathogenicity, since certain SLE-specific aAb actually exert a protective function. For example, aAb to nuclear lamin B1 are associated with thromboprotection in SLE patients by cancelling out high thrombotic risk (including strokes) associated with the presence of lupus anticoagulant aAb^16,28. (7) Finally, the criteria for aAb pathogenicity defined by Naparstek and Plotz should be applied in the evaluation of aAb associated with NP-SLE²⁹.

PITFALLS IN THE INTERPRETATION OF AUTOANTIBODY ASSOCIATIONS IN NP-SLE

Table 2 lists most autoantibodies reported in NP-SLE and associated clinical manifestations^25,30-41 (for detailed reviews^26,42). First, in general, the scientific interpretation of data in Table 2 is rendered difficult by retrospective design, small sample size of patient groups with specific NP-SLE manifestations, and the fact that most studies were reported before the ACR nomenclature and case definitions. Second, adequate disease controls with acute, subacute, and chronic neurological diseases in a sufficiently large sample size are missing in several reports, causing uncertainty as to the diagnostic specificity of several aAb for NP-SLE. Third, the lack of standardized methods for the detection of aAb associated with NP-SLE is blatant. Taken together, these weaknesses may explain in part the controversial associations between NP-SLE and certain aAb, such as anti-ribosomal P (Table 2)^38,39. The need for an international standardization of anti-ribosomal P immunoassays was recently emphasized⁴³. Fourth, because neuroblastoma cells (used in many reports) are derived from peripheral nervous system malignant cells, they are not an optimal cell line for the detection of aAb to CNS aAg²⁶. Fifth, some of the reported aAb are anticytoskeletal aAb, e.g., aAb to neurofilament proteins, glial fibrillary acid protein, and microtubule associated protein-2 (Table 2). These immune responses may be secondary to brain injury⁴⁴ and/or represent quantitative amplification of natural aAb secondary to SLE polyclonal B cell activation^45-47. Hence their claimed pathogenic role appears premature, if not unwarranted. Sixth, the lack of concurrent CSF aAb assay in studies of serum aAb limits their significance. Finally, when criteria for immunopathogenicity are used²⁹, very few reports actually demonstrate a definitive link between the presence of aAb and NP-SLE manifestations.

Table 2. Human autoantibodies associated with neuropsychiatric SLE.

A PROVOCATIVE PATHOGENIC STUDY

An exciting potential development in the immunopathogenesis of NP-SLE was the demonstration by Diamond and colleagues that a subset of anti-dsDNA from SLE patients cross-reacts with NR2 glutamate receptors in the CNS³⁴. Glutamate is the principal excitatory amino acid (EAA) neurotransmitter in the brain. Glutamate membrane receptors operate prominently in many normal neurologic functions, including cognition, mood, movement, and sensation. EEA are essential for normal neuronal function, yet they are potentially neurotoxic molecules since overstimulation of EEA receptors may lead to excitotoxic neuronal cell dysfunction and death⁹. Using murine antibodies as well as anti-dsDNA aAb obtained from the serum of a small number of SLE patients, Diamond, et al showed not only that anti-dsDNA aAb cross-reacted with NR2 glutamate receptors, but also that these aAb mediated apoptotic death of neurons in vivo and in vitro³⁴. Moreover, CSF from a single SLE patient with progressive cognitive decline contained these aAb and mediated neuronal death via an apoptotic pathway. These data suggested that SLE serum aAb may gain access to the CSF and mediate some of the non-vasculitic CNS abnormalities originally observed by Johnson and Richardson⁷. Thus far this is the only report fulfilling 4 of the 6 stringent pathogenicity criteria outlined for aAb²⁹.

Although provocative, the report remains preliminary from a diagnostic standpoint because of the small number of serum and CSF samples studied²⁷. Recent data in mice support the pathogenic role of these autoantibodies; however, no other data thus far support this clinical-serologic association in humans⁴⁸. Moreover, as reported at the recent 7th International Congress on SLE, anti-NR2 aAb did not identify cognitive dysfunction in a general SLE population⁴⁹.

CONCLUSION

Although aAb have long been suspected of playing a role in the pathogenesis of NP-SLE, we conclude that as yet none of the reported aAb has been established as pathogenic beyond any doubt²⁶. Thus, despite extensive research, NP-SLE is still a disease complex much in search of pathogenic aAb, whereas most aAb thus far described in NP-SLE are still in search of a disease.

There is clearly a major need for a multicenter international study using the ACR criteria and nomenclature for NP-SLE, and performing state of the art assays for autoantibodies to NR2 glutamate receptors and to ribosomal P protein. To our knowledge, at least one such study is under way. An international, multicenter, prospective, inception cohort study of NP-SLE has been initiated, utilizing the Systemic Lupus International Collaborating Clinics, a network of 27 international academic medical centers with a particular interest in SLE (Hanly JG, personal communication). This study, sponsored by the Canadian Institutes of Health Research, will help clarify whether specific aAb are of value for the diagnosis of NP-SLE manifestations, and may provide insights on the puzzling patient selectivity and fluctuation over time of NP-SLE manifestations.

As shown by the work of Diamond and colleagues³⁴, the key to establishing an immunopathogenic role for aAb in NP-SLE is to determine the effects of specific aAb on brain function. An SLE brain bank is being developed at Cornell University, New York, and information can be obtained from Bruce Volpe, MD (bvolpe@burke.org). Several potential research avenues have been suggested by Moore²⁶. Much research thus far has focused only on single aAb. However, given the multiple aAb present in SLE, mechanistic research models should focus more on the added pathogenicity resulting from the interplay between several antibodies, cytokines, and immunocompetent cells^22,50.

Finally, understanding of the exceptional complexity of the nervous systems and of NP-SLE dictates multidisciplinary research approaches bringing together clinical and basic scientists from the disciplines of rheumatology, immunology, and neuroscience. Such approaches offer the greatest hope for developing novel therapies for NP-SLE with fewer adverse effects⁵¹.

REFERENCES

Search PubMed for:

2. Meroni PL, Tincani A, Sepp N, et al. Endothelium and the brain in CNS lupus. Lupus 2003;12:919-28. [MEDLINE]

3. Trysberg E, Carlsten H, Tarkowski A. Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 2000;9:498-503. [MEDLINE]

4. Svenungsson E, Andersson M, Brundin L, et al. Increased levels of proinflammatory cytokines and nitric oxide metabolites in neuropsychiatric lupus erythematosus. Ann Rheum Dis 2001;60:372-9. [MEDLINE]

5. Dellalibera-Joviliano R, Dos Reis ML, Cunha FQ, Donadi EA. Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus. J Rheumatol 2003;30:485-92. [MEDLINE]

6. Denburg SD, Denburg JA. Cognitive dysfunctions in SLE. In: Lahita R, editor. Systemic lupus erythematosus. 3rd ed. Toronto: Academic Press; 1999:611-29.

7. Johnson RT, Richardson EP. The neurological manifestations of SLE. A clinico-pathological study of 24 cases and review of the literature. Medicine 1968;47:337-69.

8. Feinglass EJ, Arnett FC, Dorsch CA, Zizic TM, Stevens MB. Neuropsychiatric manifestations of SLE: diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine 1976;55:323-39.

9. Moore PM. Neuropsychiatric SLE. In: Lahita R, editor. Systemic lupus erythematosus. 3rd ed. Toronto: Academic Press; 1999: 575-601.

10. Hanly JG, Cassell K, Fisk JD. Cognitive function in systemic lupus erythematosus: results of a 5-year prospective study. Arthritis Rheum 1997;40:1542-3. [MEDLINE]

11. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599-608. [MEDLINE]

12. Hanly JG, McCurdy G, Fougère L, Douglas JA, Thompson K. Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance. J Rheumatol 2004;31:2156-62.

13. Nived O, Sturfelt G, Liang MH, De Pablo P. The ACR nomenclature for CNS lupus revisited. Lupus 2003;12:872-6. [MEDLINE]

14. Ainiala H, Hietaharju A, Loukkola J, et al. Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum 2001;45:419-23. [MEDLINE]

15. Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003;30:985-92. [MEDLINE]

16. Senecal JL, Rauch J, Grodzicky T, et al. Strong association of autoantibodies to human nuclear lamin B1 with lupus anticoagulant antibodies in systemic lupus erythematosus. Arthritis Rheum 1999;42:1347–53. [MEDLINE]

17. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7. [MEDLINE]

18. Hahn BH. Antibodies to DNA. N Engl J Med 1998;338:1359-68. [MEDLINE]

19. Hahn BH, Tsao BP. Antibodies to DNA. In: Wallace DJ, Hahn BH, editors. Dubois' lupus erythematosus. Philadelphia: Lippincott, Williams & Wilkins; 2002:423-45.

20. Peeva E, Diamond B, Putterman C. The structure and derivation of antibodies and autoantibodies. In: Wallace DJ, Hahn BH, editors. Dubois' lupus erythematosus. Philadelphia: Lippincott, Williams & Wilkins; 2002:391-413.

21. Koren E, Koscec M, Wolfson-Reichlin M, et al. Murine and human antibodies to native DNA that cross-react with the A and D SnRNP polypeptides cause direct injury of cultured kidney cells. J Immunol 1995;154:4857-64. [MEDLINE]

22. Clancy RM, Askanase AC, Kapur RP, et al. Transdifferentiation of cardiac fibroblasts, a fetal factor in anti-SSA/Ro-SSB/La antibody-mediated congenital heart block. J Immunol 2002;169:2156-63. [MEDLINE]

23. Casciola-Rosen L, Anhah G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994;179:1317-30. [MEDLINE]

24. Dutz JP, Sontheimer RD. Pathomechanisms of cutaneous lupus eythematosus. In: Wallace DJ, Hahn BH, editors. Dubois' lupus erythematosus. Philadelphia: Lippincott, Williams & Wilkins; 2002:549-71.

25. Bluestein HG, Williams GW. Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med 1981;70:240-6. [MEDLINE]

26. Moore PM. Autoantibodies, autoantigens, and nervous system. In: Wallace DJ, Hahn BH, editors. Dubois' lupus erythematosus. Philadelphia: Lippincott, Williams & Wilkins; 2002.

26a Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annu Rev Neurosci 1999;22:11-28.[MEDLINE]

27. Kotzin BI, Kozora E. Anti-DNA meets NMDA in neuropsychiatric lupus. Nature Medicine 2001;7:1175-6. [MEDLINE]

28. Dieude M, Senécal JL, Rauch J, et al. Association of autoantibodies to nuclear lamin B1 with thromboprotection in systemic lupus erythematosus. Lack of evidence for a direct role of lamin B1 in apoptotic blebs. Arthritis Rheum 2002;46:2695-707. [MEDLINE]

29. Naparstek Y, Plotz PH. The role of autoantibodies in autoimmune disease. Ann Rev Immunol 1993;11:79-104. [MEDLINE]

30. Robbins M, Kornguth SE, Bell CL, et al. Antineurofilament antibody evaluation in neuropsychiatric systemic lupus erythematosus. Combination with anticardiolipin antibody assay and magnetic resonance imaging. Arthritis Rheum 1988;31:623-31. [MEDLINE]

31. Sanna G, Piga M, Terryberry JW, et al. Central nervous system involvement in systemic lupus erythematosus: cerebral imaging and serological profile in patients with and without overt neuropsychiatric manifestations. Lupus 2000;9:573-83. [MEDLINE]

32. Hanly JG, Hong C, White TD. Brain reactive autoantibodies and cognitive impairment in systemic lupus erythematosus. Lupus 1994;3:193-9. [MEDLINE]

33. Williams RC Jr, Sugiura K, Tan EM. Antibodies to microtubule-associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2004;50:1239-47. [MEDLINE]

34. DeGiorgio L, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nature Medicine 2001;7:1189-93. [MEDLINE]

35. Hanly JG, Hong C, Smith S, Fisk JD. A prospective analysis of cognitive dysfunction and anticardiolipin antibodies in SLE. Arthritis Rheum 1999;42:728-34. [MEDLINE]

36. Shoenfeld Y, Lev S, Blatt I, et al. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 2004;31:1344-8. [MEDLINE]

37. Denburg JA. Neuronal antibodies. In: Peter JB, Shoenfeld Y, editors. Autoantibodies. Amsterdam: Elsevier Science; 1996: 546-50.

38. Reichlin M. Ribosomal P antibodies and central nervous system lupus. Lupus 2003;12:916-8. [MEDLINE]

39. Mahler M, Kessenbrock K, Raats J, Williams R, Fritzler MJ, Bluthner M. Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins. J Mol Med 2003;81:194-204. [MEDLINE]

40. Galeazzi M, Annunziata P, Sebastiani GD, et al. Anti-ganglioside antibodies in a large cohort of European patients with systemic lupus erythematosus: clinical, serological, and HLA class II gene associations. J Rheumatol 2000;27:135-41. [MEDLINE]

41. Martinez X, Tintore M, Montalban J, Ordi J, Vilardell M, Codina A. Antibodies against gangliosides in patients with systemic lupus erythematosus and neurological manifestations. Lupus 1992;1:299-302. [MEDLINE]

42. Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH. Autoantibodies in neuropsychiatric lupus. Autoimmunity 2002;35:79-86. [MEDLINE]

43. Mahler M, Kessenbrock K, Raats J, Fritzler MJ. Technical and clinical evaluation of anti-ribosomal P protein immunoassays. J Clin Lab Anal 2004;18:215-23. [MEDLINE]

44. Trysberg E, Nylen K, Rosengren LE, Tarkowski A. Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthritis Rheum 2003;48:2881-7. [MEDLINE]

45. Senecal JL, Ichiki S, Girard D, Raymond Y. Autoantibodies to nuclear lamins and to intermediate filament proteins: natural, pathologic or pathogenic? J Rheumatol 1993;20:211-9. [MEDLINE]

46. Senecal JL, Oliver JM, Rothfield NF. Anticytoskeletal autoantibodies in the connective tissue diseases. Arthritis Rheum 1985;28:889-98. [MEDLINE]

47. Senecal JL, Rauch J. Hybridoma lupus autoantibodies can bind major cytoskeletal filaments in the absence of DNA-binding. Arthritis Rheum 1988;31:864-75. [MEDLINE]

48. Kowal C, DeGiorgio LA, Nakaoka T, et al: Cognition and immunity; antibody impairs memory. Immunity 2004;21:179-88. [MEDLINE]

49. Harrison MJ, Ravdin L, Volpe B, Diamond B, Lockshin M. Anti-NR2 antibody does not identify cognitive dysfunction in a general SLE population. Abstract Book of the 7th International Congress on SLE and related conditions, New York, NY, 9-13 May, 2004.

50. Dieude M, Senécal JL, Raymond Y. Induction of endothelial cell apoptosis by heat-shock protein 60-reactive antibodies from anti-endothelial cell autoantibody-positive systemic lupus erythematosus patients. Arthritis Rheum 2004;in press.

51. Brey RL, Petri MA. Neuropsychiatric systemic lupus erythematosus: miles to go before we sleep. Neurology 2003;61:9-10. [MEDLINE]