Neurolupus is associated with anti-ribosomal P protein antibodies: An inception cohort study

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Abstract

Objective

Serum IgG antibodies (Abs) to phosphorylated ribosomal (P ribosomal) proteins have been inconsistently associated with neuropsychiatric manifestations in systemic lupus erythematosus (SLE). Our aim was to assess whether serum IgG Abs to ribosomal P proteins are associated with neuropsychiatric SLE.

Patients and methods

We examined an inception cohort of 219 SLE patients. Neuropsychiatric SLE manifestations were characterized using the American College of Rheumatology (ACR) definition. Serum Abs to P ribosomal proteins were searched for by immunoblotting. In a subgroup of patients, Abs were investigated also in cerebrospinal fluid (CSF).

Results

Abs to P ribosomal proteins were detected in 45 (21%) patients, 23 of whom (51%) with neuropsychiatric involvement. Abs to P ribosomal protein were present both in serum and CSF. Abs to P ribosomal proteins significantly correlated with psychosis (p = 0.017), mononeuropathy multiplex (p = 0.040), malar rash (p = 0.004), serum anti-Sm Abs (p = 0.042), and lupus anticoagulant (p = 0.036). SLE onset age was significantly younger in patients with Abs to P ribosomal proteins. Logistic regression analysis confirmed the relationship between Abs to P ribosomal proteins and psychosis, malar rash, SLE onset age and lupus anticoagulant.

Conclusions

Abs to ribosomal P proteins are associated with psychosis and might be associated with peripheral nervous system complications.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical manifestations. Central nervous system (CNS) involvement occurs in up to 80% of SLE patients [1], [2], [3], [4], [5] the large difference in frequency mostly depending on the diagnostic criteria [6], [7], [8], the considered population, the study design, and antibody assay used.

Neuropsychiatric SLE (NPSLE) includes neurological syndromes of central, peripheral, and autonomic nervous system observed in patients with SLE not due to infections, hypertension, metabolic abnormalities or drug toxicity. These manifestations may precede the onset of SLE or occur at anytime during the course of the disease. In 1999, the American College of Rheumatology (ACR) proposed a standard nomenclature for NPSLE, with case definitions of 19 neuropsychiatric syndromes including seizures, stroke, headache, polyneuropathy, mononeuropathy, depression, and psychosis [9].

The pathogenesis of NPSLE is still unknown, but several autoantibodies (Abs) directed to nuclear as well as cytoplasmic antigens have been suggested to play a role [10], [11], [12], [13].

Phosphorylated ribosomal (P ribosomal) proteins are three ubiquitous, highly conserved acidic phosphoproteins (P0, P1, P2) of different molecular weights (38 kDa, 17 kDa, and 15 kDa) forming the stalk of the 60S ribosomal subunit, where they play a role in protein synthesis. They share a 22 amino acid carboxyl-terminus which contains an immunodominant epitope. The ribosomal protein P0 immunolocalizes on the membrane surface of neuronal, hepatic, and endothelial cells, in an immunological accessible way [14].

Abs to the P ribosomal proteins are considered a highly specific marker of SLE and appear to correlate with disease activity, liver, kidney as well as with CNS involvement [15].

Abs to P ribosomal proteins were first reported to be associated with NPSLE in 1987, when Bonfa et al. described serum IgG to P ribosomal proteins in 18 of 20 patients with neuropsychiatric manifestations. In 2 cases the Abs serum level correlated with disease activity [16]. Subsequent studies gave, however, inconsistent results [17], [18], [19], [20]. Two recent international multicentre studies, carried out on a very large number of SLE patients, led to opposite results [21], [22].

Interestingly, an animal model of autoimmune depression has recently been developed by injecting anti-P ribosomal Abs in cerebral ventriculi of mice [23]. In addition it has been suggested that anti-P ribosomal mediated damage could derive from neuronal apoptosis [24].

The objective of our study was to investigate whether the presence of serum Abs to ribosomal P proteins in SLE patients correlates with NPSLE manifestations using a large inception cohort of patients followed in a single centre. Moreover, in a subgroup of patients we also analyzed whether Abs to P ribosomal proteins were detectable in the cerebrospinal fluid (CSF) and whether their presence was related to blood–brain barrier alterations.

Section snippets

Patients

We considered an inception cohort of 219 consecutive patients affected with SLE recruited in a single Rheumatologic Unit of the University of Padua, and followed-up from 1986 to October 2004. They were all Caucasian, 185 women and 34 men, mean age at diagnosis 28 ± 10.4 years (range 10–66). The median follow-up was 110 months (range 1–18 years).

All patients fulfilled at least four of the ACR criteria for SLE classification.

SLE-associated clinical manifestations, occurring anytime during the

Serum Abs to ribosomal P proteins and clinical and serological correlations

IgG Abs to P ribosomal proteins were present anytime in 45 (21%) of the 219 SLE patients (Fig. 1B). The SLE age at onset was significantly younger in patients with Abs to P ribosomal proteins than in those without (23.2 ± 7.4 vs 26.7 ± 10.5 years, p = 0.04). Of the 45 patients with Abs to P ribosomal proteins, 23 (51%) had neurological manifestations: 19 (42%) CNS involvement including 8 (17%) headache, 4 (8%) cerebrovascular disease, 4 (8%) psychiatric disorders (3 depression, one psychosis), one

Discussion

The results of our study confirm the association between NPSLE and Abs to P ribosomal proteins using an inception cohort of patients, homogeneous in respect to race, followed-up in a single centre for a median period of 10 years. Moreover, our results suggest that even peripheral nervous system manifestations attributable to SLE may be related to Abs to P ribosomal proteins.

Firstly described by Bonfa et al. [16] the relationship between psychosis and Abs to P ribosomal proteins became

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