Background Arthritis is known to associate with upregulation of inflammatory mediators in the central nervous system (CNS) as shown in earlier experimental studies (1). However, little is known about the possible presence of intrathecal immune activation in RA patients, which may have importance for cerebral symptoms, such as fatigue.
Objectives Here we sought to investigate potential specific immune activation in RA CNS, focusing on the detection of anti-citrullinated protein antibodies (ACPA), known to be highly specific and predictive for the development of RA.
Methods Thirteen female patients with ACPA-positive RA underwent lumbar puncture and collection of CSF and serum. CSF from 10 age-matched individuals with no neuroinflammatory or rheumatic disease, and 26 age-matched patients with multiple sclerosis (MS), were included as controls. IgG ACPAs were measured using a commercial anti-CCP2 ELISA assay (Euro-Diagnostica, Malmö, Sweden). Serum samples were diluted 1:100 according to the protocol, while CSF samples were used undiluted. Analyses of CSF albumin and CSF/plasma albumin ratios were performed in clinical routine.
Results As expected, all RA patients were anti-CCP positive in serum (threshold for positivity: 25U/ml), with levels ranging from 34U/ml to 3200U/ml. Interestingly, 7/13 RA patients were anti-CCP positive also in CSF, with levels ranging from 29U/ml to 154U/ml in undiluted samples. Anti-CCP levels in controls, on the other hand, were significantly lower; 2.19±0.09U/ml for non-inflammatory controls, and 2.54±0.16U/ml for MS patients (undiluted samples). In RA patients, there was a correlation between presence of anti-CCP antibodies in CSF and significantly higher serum anti-CCP levels (1453±82U/ml in RA with CCP positivity both serum/CSF versus 90±46U/ml; CCP negative in CSF, p<0.01). No difference in CSF albumin or the CSF/plasma albumin ratio could be detected between these two RA groups. All RA patients had normal CSF albumine and CSF/plasma albumine ratios, consistent with an intact blood brain barrier. No RA patient had any history of, or symptoms of, neurologic disease.
Conclusions Our data show, for the first time, the presence of ACPAs in CSF of RA patients. The association with high serum ACPA levels in these patients may suggest a leakage of antibodies, though data demonstrate intact blood brain barriers. Interestingly, certain ACPA specificities are known to recognize the citrullinated form of the neuronal antigen myelinic base protein (cit-MBP) (2). Moreover, endogenous cit-MBP is thought to be play an important role in the autoimmune mechanisms of multiple sclerosis (3). Thus, presence of autoantibodies like ACPAs in RA CSF may predispose for autoimmune reactions in the central nervous system, potentially affecting fatigue and other cerebral symptoms.
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Ioan-Facsinay A et al, Ann Rheum Dis 2011;70:188–193
Moscarello MA et al, Neurochem Res (2007) 32:251–256
Disclosure of Interest None Declared
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