Central nervous system involvement as a major manifestation of rheumatoid arthritis

A 58-year-old woman with an 8-year history of seropositive rheumatoid arthritis was admitted with right hemiparesis, history of seizures, fever, weight loss and headaches. Her blood tests revealed the presence of rheumatoid factor, elevated C-reactive protein and anti-cyclic citrullinated peptide antibodies (>200 RU/ml). Examination of cerebrospinal fluid demonstrated pleocytosis (118 cells/mm³, predominantly lymphocytes) with elevated protein level (58 mg/dl); cultures were negative. Magnetic resonance imaging findings were suggestive for meningoencephalitis. Short course of high-dose corticosteroids and cyclophosphamide led to clinical improvement. Rheumatoid vasculitis was probably responsible for neurological symptoms.     

Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation

OBJECTIVE: To assess the validity of the recently developed American College of Rheumatology (ACR) nomenclature for neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: We conducted a cross-sectional, population-based study covering an area with 440,000 people. A total of 46 patients aged 16 to 65 years fulfilled the criteria for a definite diagnosis of SLE. One control for each patient matched by age, sex, education, and place of residence was randomly identified from the population register. All patients and controls underwent a clinical neurologic examination and neuropsychological testing. The data were analyzed using conditional logistic regression methods. RESULTS: Forty-two patients (91%) and 25 controls (56%) fulfilled at least one of the ACR NPSLE criteria, which gave an odds ratio (OR) of 9.5 (95% confidence interval [CI] 2.2-40.8) but low specificity (0.46). Cognitive dysfunction was the most common syndrome detected in 37 patients (80%). A revised set of 16 criteria excluding the syndromes without evidence for neuronal damage resulted in improved specificity (OR 7.0, 95% CI 2.1-23.5, specificity 0.93). CONCLUSION: The proposed 19 ACR criteria did not differentiate SLE patients from controls, nor NPSLE patients from other SLE patients. The revised NPSLE criteria proposed by us performed well in our population but should be evaluated in a larger patient population.     

Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population‐based evaluation

Objective

To assess the validity of the recently developed American College of Rheumatology (ACR) nomenclature for neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods

We conducted a cross‐sectional, population‐based study covering an area with 440,000 people. A total of 46 patients aged 16 to 65 years fulfilled the criteria for a definite diagnosis of SLE. One control for each patient matched by age, sex, education, and place of residence was randomly identified from the population register. All patients and controls underwent a clinical neurologic examination and neuropsychological testing. The data were analyzed using conditional logistic regression methods.

Results

Forty‐two patients (91%) and 25 controls (56%) fulfilled at least one of the ACR NPSLE criteria, which gave an odds ratio (OR) of 9.5 (95% confidence interval [CI] 2.2–40.8) but low specificity (0.46). Cognitive dysfunction was the most common syndrome detected in 37 patients (80%). A revised set of 16 criteria excluding the syndromes without evidence for neuronal damage resulted in improved specificity (OR 7.0, 95% CI 2.1–23.5, specificity 0.93).

Conclusion

The proposed 19 ACR criteria did not differentiate SLE patients from controls, nor NPSLE patients from other SLE patients. The revised NPSLE criteria proposed by us performed well in our population but should be evaluated in a larger patient population.

     

Central nervous system involvement in systemic lupus erythematosus: Data from the Spanish Society of Rheumatology Lupus Register (RELESSER)

ObjectivesTo analyze the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE).MethodsPatients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cerebrovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders.ResultsA total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.29–2.67) and more specifically CVD (HR 2.17, 1.41–3.33) and organic brain syndrome (HR 2.11, 1.19–3.74) accounted as independent prognostic factors for poor survival.ConclusionThe presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD and organic brain syndrome are associated with the highest mortality rates.     

Central nervous system involvement in systemic lupus erythematosus: cerebral imaging and serological profile in patients with and without overt neuropsychiatric manifestations

The aim of this study was to evaluate morphological and functional abnormalities by cerebral imaging in a series of systemic lupus erythematosus (SLE) patients with and without overt central nervous system (CNS) manifestations, and to detect possible relationships with clinical parameters and a large panel of autoantibodies, including those reactive against neurotypic and gliotypic antigens. 68 patients with SLE were investigated in a cross-sectional study which included clinical evaluation of symptoms, cerebral magnetic resonance imaging (MRI) and brain single photon emission tomography (SPECT) analysis, electroencephalography (EEG), and serological tests for antibodies directed against nuclear, cytoplasmic neuronal and glial cell-related antigens. The results of this study showed: (1) a significant positive association of (a) anti-glial fibrillary acidic protein (GFAP) serum antibodies with neuropsychiatric (NP) manifestations and (b) anti-serin proteinase 3 (anti-PR3/c-ANCA) serum antibodies with pathological cerebral SPECT; (2) the presence of significantly higher values of (a) SLICC organ damage index in patients with abnormal MRI and (b) SLAM activity index in patients with abnormal SPECT; and (3) the association of (a) abnormal MRI with nonactive NP manifestations and (b) combined abnormality of brain SPECT and MRI with the occurrence of overall overt NP manifestations and with those of the organic/major type. Neuropsychiatric manifestations, namely those of the organic/major type, appeared to be significantly associated to the presence of a serum antibody against GFAP, a gliotypic antigen. There was also evidence of an association between SPECT abnormality and the presence of anti-PR3 (c-ANCA). Furthermore, brain imaging by MRI and SPECT applied to SLE patients appears to express CNS involvement significantly related to specific categories of NP manifestations. The abnormalities detected by the two tests seem to be preferentially associated with different activity phases of the NP disorder or of the lupus disease.     

Flow cytometric assessment of anti-neuronal antibodies in central nervous system involvement of systemic lupus erythematosus and other autoimmune diseases

The objective of this study is to evaluate the association between anti-neuronal antibody (anti-NA) and central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE) and other rheumatic diseases using a flow cytometric method. Anti-NA was measured by flow cytometry in serum and cerebrospinal fluid (CSF) samples from patients with SLE (n=44 for serum, n=17 for CSF), other rheumatic diseases (n=64 for serum, n=21 for CSF) and from healthy controls (n=65 for serum, n=18 for CSF). Serum anti-NA was more frequently observed in SLE (31.8%, 14/44) than in other rheumatic diseases (4.7%, 3/64, P<0.001) or in healthy controls (0%, 0/65, P<0.00001). In SLE patients, the frequency of serum anti-NA was significantly higher in CNS-SLE (76.5%, 13/17) than in non CNS-SLE (3.7%, 1/27, P<0.000001). CSF anti-NA was detected in 88.2% (15/17) of CNS-SLE and was more frequently detected in CNS-SLE (15/17, 88.2%) than in other rheumatic diseases with CNS involvement (1/21, 4.8%, P<0.000001) or in healthy controls (0/18, P<0.000001). In conclusion, serum anti-NA was more frequently found in CNS-SLE than in non CNS-SLE, other rheumatic diseases or in healthy controls. The frequency of CSF anti-NA in CNS-SLE was significantly higher than in other rheumatic diseases with CNS involvement or in healthy controls.     

Reliability and validity of the proposed American College of Rheumatology neuropsychological battery for systemic lupus erythematosus

OBJECTIVE: To examine the reliability and validity of the proposed American College of Rheumatology (ACR) neuropsychological battery for patients with systemic lupus erythematosus (SLE). METHODS: Thirty-one SLE patients with a history of neuropsychiatric symptoms (NPSLE), 22 SLE patients without a history of neuropsychiatric symptoms (non-NPSLE), and 25 healthy controls completed measures of cognition at baseline and after 1 month. The 1-hour proposed ACR-SLE battery was compared with a 4-hour comprehensive battery (CB). RESULTS: Seven of 12 measures from the ACR-SLE battery were lower in SLE patients compared with controls. Overall agreement between impairment on the ACR-SLE battery and the CB was 90%. This was established using previously defined impairment on the CB and 4 of 12 scores impaired on the ACR-SLE battery. Almost perfect agreement between the 2 batteries was found for non-NPSLE patients and healthy controls (95-96%) and moderate agreement was reported for NPSLE patients (81%). Intraclass correlation coefficients for ACR-SLE tests ranged from 0.40 to 0.90, indicating adequate reliability. CONCLUSION: Reliability and validity of the ACR-SLE battery was established in this study. Agreement regarding classification for impairment was almost perfect for non-NPSLE and moderate for the NPSLE patients. The ACR battery is well designed for general classification of cognitive impairment in SLE. However, comprehensive testing may be useful in identifying specific deficits in NPSLE.     

Clinical characteristics of COVID-19 patients with underlying rheumatic diseases in Japan: data from a multicenter observational study using the COVID-19 Global Rheumatology Alliance physician-reported registry

Clinical Rheumatology - To describe clinical characteristics of patients in Japan with coronavirus disease 19 (COVID-19) and pre-existing rheumatic disease and examine the possible risk factors...     

Central nervous system lupus erythematosus: the value of magnetic resonance imaging

Magnetic resonance imaging was sued to examine the brains of 13 patients with systemic lupus erythematosus (SLE) who had experienced symptoms and signs of encephalopathy. All the patients had normal computerized tomographic scans. Four patients with abnormal magnetic resonance imaging studies had active central nervous system disease. None of the 9 patients with normal scans had active nervous system involvement at the time of study. Parenchymal lesions were usually located in the region of the corticomedullary junction or in the deep periventricular white matter. In coronal sections, some of the corticomedullary lesions extended centripetally as thin irregular lines into the white matter approximating the course of penetrating arterioles of the brain. The parenchymal lesions resolved in 4 months in 1 patient, but persisted unchanged in the others despite clinical improvement or a stable clinical course. It is likely that the parenchymal lesions of these patients represent intrinsic vasculopathy of small cerebral vessels and perivascular microinfarctions associated with SLE.     

The American College of Rheumatology criteria for the classification of systemic lupus erythematosus: strengths, weaknesses, and opportunities for improvement

The American College of Rheumatology classification criteria were developed to operationalize the definition of systemic lupus erythematosus (SLE) to allow comparison of clinical research from different centers, but also serve to facilitate education and to guide clinical practice. The classification criteria have been critical to research, but should be viewed as a temporary step until improved understanding of the pathogenesis of SLE emerges. Criteria have inherent limitations, including bias towards more severe and longer duration disease, equal weighting of features that vary in clinical significance, and exclusion of patients with SLE from research because they do not meet criteria. For some SLE research questions, it may be appropriate to include patients diagnosed with SLE who do not meet criteria, if these patients' manifestations and criteria are documented explicitly. SLE disease activity, cumulative organ damage, disease duration, criteria ever met, and criteria met at time of enrollment are important data that should be presented in clinical studies of SLE regardless of the number of criteria met. The criteria should be reevaluated periodically, utilizing patients and controls with a range of diseases and disease severity. A simplified weighting system may more accurately reflect clinical practice.     

Central nervous system involvement in rheumatoid arthritis patients and the potential implications of using biological agents

Central nervous system (CNS) involvement is quite unusual in patients with rheumatoid arthritis (RA), although cerebral vasculitis, rheumatoid nodules and meningitis have all been reported, and patients with RA may also have CNS comorbidities such as stroke and neuro-degenerative and demyelinating syndromes. It has been found that biological drugs, especially anti-tumour necrosis factor-alpha (anti-TNF-α) drugs, slightly increase the risk of developing demyelinating diseases, and they are consequently discouraged in patients with multiple sclerosis and related disorders. Furthermore, the risk of opportunistic CNS infections is increased in immunosuppressed patients.To review the current literature concerning CNS involvement in patients with RA (including RA-related forms and comorbidities) and the incidence of new-onset CNS diseases in patients with RA undergoing biological treatment (anti-TNF or non-anti-TNF drugs), the Medline database was searched using the key words ‘rheumatoid arthritis’, ‘central nervous system’, ‘anti-TNF’, ‘abatacept’, ‘tocilizumab’, ‘rituximab’ and ‘anakinra’. Abstracts not in English were excluded.We selected 76 articles published between 1989 and 2017, which were divided into four groups on the basis of whether CNS involvement was RA-related or not and according to the type of biological agent used (TNF inhibitors or other agents). The RA-related diseases included aseptic meningitis, vasculitis and cerebral rheumatoid nodules, which benefit from immunosuppressive treatments. CNS comorbidities included stroke, seizures, dementia and neuropsychiatric disorders, which have been frequently described in biological agent-naïve patients with RA, and other rarely reported neurological diseases, such as extra-pyramidal syndromes and demyelinating disorders. CNS comorbidities are relatively frequent among patients with RA and may be related to systemic inflammation or concomitant medications. The use of anti-TNF drugs is associated with the risk of developing demyelinating diseases, and CNS infections have been described in patients treated with anti-TNF and non-anti-TNF agents. Non-anti-TNF drugs may be preferred in the case of demyelinating diseases, cerebral vasculitis or neurolupus.Patients with RA may suffer from CNS involvement as a manifestation of RA or as a comorbidity. The treatment of such medical conditions should be guided on the basis of their etiopathogenesis: steroids and immunosuppressants are useful in the case of RA-related CNS diseases but are often detrimental in other situations. Similarly, the choice of biological agents in patients with RA with CNS complications should be guided by a correct diagnosis in order to prevent further complications.     

Central nervous system control of pituitary vasopressin receptors: evidence for involvement of multiple factors

The regulation of pituitary vasopressin (VP) receptor concentration was investigated in rats with antero-lateral cuts (ALC) placed around the hypothalamus, as well as in Brattleboro homozygotes (HO) that genetically suffer from a lack of AVP. Hypothalamic ALCs caused a reduction in (3H)-AVP binding, while counteracting the dramatic fall in binding that normally occurs after adrenalectomy. Surprisingly, in HO rats, long-term adrenalectomy did cause pituitary AVP receptor number to decrease to an extent similar to that seen in normal rats. However, the receptor disappeared twice as rapidly in heterozygote controls than in HO animals, with calculated half-lives of 1.1 and 2.0 days, respectively. In HO, chronic administration of VP reduced receptor concentration by about 80%, while the same dose of oxytocin (OT) produced only a 20-30% reduction. Whereas dexamethasone injections did reverse the depressing effect of adrenalectomy on pituitary AVP receptors, they failed to enhance binding in sham-operated controls, treated or not with VP; thereby suggesting a central site of action of the steroid. In contrast, in rats with hypothalamic ALCs (i.e. with the pituitary lacking central control), corticosterone implants did antagonize the reduction in receptor density caused by adrenalectomy. We conclude that the pituitary AVP receptor system lies mainly under control of the central nervous system, through a mechanism of action that not only seems to imply AVP and OT, but probably also some other hypothalamic factor(s). Glucocorticoids appear to exert a dual effect, acting indirectly through negative feedback control of neuropeptide release and, possibly, also directly on the pituitary to regulate binding sites.