Elaine L. Alexander

Sjögren's Syndrome: Association of Anti-Ro(SS-A) Antibodies with Vasculitis, Hematologic Abnormalities, and Serologic Hyperreactivity

The clinical significance of autoantibodies to Ro(SS-A) and La(SS-B) in Sjögrens syndrome was examined in a retrospective evaluation of 75 patients with symptoms of the sicca complex who had either primary Sjögrens syndrome or Sjögrens syndrome associated with another connective tissue disease. The clinical, hematologic, and serologic features associated with autoantibodies to the small molecular weight ribonucleoproteins Ro(SS-A) and La(SS-B) were ascertained. A striking clinical association of anti-Ro(SS-A) antibodies (found in 33 patients) with extraglandular disease (vasculitis, purpura, and lymphadenopathy) was seen. Hematologic abnormalities (anemia, leukopenia, and thrombocytopenia) were also associated with the presence of anti-Ro(SS-A) antibodies. Furthermore, anti-Ro(SS-A) antibody was associated with hyperglobulinemia, increased serologic reactivity in terms of rheumatoid and antinuclear factors, cryoglobulinemia, and hypocomplementemia. The presence of anti-Ro(SS-A) antibodies defines a subset of patients with Sjögrens syndrome who have systemic clinical manifestations including vasculitis, hematologic abnormalities, and serologic hyperreactivity.

Primary Sjögren's Syndrome with Central Nervous System Disease Mimicking Multiple Sclerosis

Central nervous system involvement has occurred in approximately 20% of patients with primary Sjögrens syndrome evaluated at our institution. Characteristically, the neurologic dysfunction is multifocal, involving both the brain and spinal cord, and is recurrent over time. We present the features of 20 patients with primary Sjögrens syndrome and central nervous system involvement whose neurologic findings, evoked potential abnormalities, and cerebrospinal fluid profiles (elevated IgG indices, oligoclonal bands on agarose gel electrophoresis, and mild pleocytosis with reactive lymphoid cells) closely resembled those of multiple sclerosis. In fact, multiple sclerosis was considered the most likely diagnosis in each of these patients before diagnosis of Sjögrens syndrome, and each patient met criteria for definite multiple sclerosis. The clinical effects of corticosteroid treatment during episodes of acute neurologic dysfunction appeared to be beneficial in these patients.

Sjögren syndrome Central nervous system manifestations

we studied eight patients who had primary Sjogren syndrome and central nervous system (CNS) disorders that were not attributable to other causes. Focal cerebral deficits were observed in five patients. Aseptic meningoencephalitis was seen in five patients, recurrent in one. Spinal cord manifestations in three patients took several forms: acute transverse myelitis, chronic progressive myelopathy, and spinal subarachnoid hemorrhage. Precipitating antibodies to the Ro(SSA) cytoplasmic antigen were detected in the sera of seven of eight patients. This may be relevant to the pathogenesis of CNS disease in Sjogren syndrome, because there is a strong correlation between vasculitis and the presence of anti-Ro(SSA) antibodies in this connective tissue disorder.

Neurologic Complications of Primary Sj??gren??s Syndrome

Although peripheral nervous system disease has been well documented in Sjögrens syndrome (SS), central nervous system (CNS) involvement is considered distinctly uncommon. Sixteen patients with primary SS and CNS disorders not attributable to other causes were the subjects of this study. Cerebral manifestations, both focal and diffuse, as well as spinal cord disease, were observed. Peripheral vasculitis occurred in 12 patients (75%), 83% of whom had anti-Ro(SSA) antibodies. The high proportion of patients with concomitant peripheral vasculitis, and the observed association with antibodies to the Ro(SSA) antigen system which, in other studies, has been linked to vasculitis in SS, suggest that an immune vasculopathy may play a role in the pathogenesis of the CNS disease of SS.

Anti-Ro(SS-A) autoantibodies in central nervous system disease associated with Sjögren's syndrome (CNS-SS): Clinical, neuroimaging, and angiographic correlates

Objective: To examine in Sjögrens syndrome (SS) the interrelationship between the presence of the anti-Ro(SS-A) antibody response and (1) concomitant presence and type (ie, focal or nonfocal) of CNS disease (CNS-SS), (2) cross-sectional brain MRI or CT, and (3) abnormal cerebral angiography. Methods: Neurologic, neuroimaging, and angiographic features of CNS-SS patients were correlated with the presence of precipitating anti-Ro(SS-A) autoantibodies detected by gel double-immunodiffusion or quantitative ELISA, which detects antibodies directed against the 60-kd peptide. Statistical analyses were performed using Fishers exact test (two-tailed) with Haldanes adjustment and odds ratio with Cornfield 95% confidence intervals. Results: Precipitating antibodies against the Ro(SS-A) antigen, determined by gel double-immunodiffusion, were present in an increased frequency in CNS-SS patients with (1) documented clinical CNS disease, (2) focal clinical CNS manifestations and serious complications, (3) large regions of increased signal intensity, consistent with ischemia/infarcts on brain MRI scans or regions of decreased attenuation consistent with infarcts on CT, and (4) abnormal cerebral angiograms consistent with small-vessel angiitis. Finally, the anti-Ro(SS-A) antibody response in CNS was directed against the 60-kd peptide specificity, determined by ELISA. Conclusions: Clinical, neuroimaging (cerebral CT), and angiographic observation suggest that a subset of anti-Ro(SS-A) antibody-positive, in contrast with negative, CNS-SS patients have more serious and extensive CNS disease, some with frank cerebral angiopathy. Anti-Ro(SS-A) antibodies are postulated to play a role in mediating or potentiating vascular injury in CNS-SS.

Reversible Cold-Induced Abnormalities in Myocardial Perfusion and Function in Systemic Sclerosis

The effects of peripheral cold exposure on myocardial perfusion and function were studied in 13 patients with scleroderma without clinically evident myocardial disease. Ten patients had at least one transient, cold-induced, myocardial perfusion defect visualized by thallium-201 scintigraphy, and 12 had reversible, cold-induced, segmental left ventricular hypokinesis by two-dimensional echocardiography. The 10 patients with transient perfusion defects all had anatomically corresponding ventricular wall motion abnormalities. No one in either of two control groups (9 normal volunteers and 7 patients with chest pain and normal coronary arteriograms) had cold-induced abnormalities. This study is the first to show the simultaneous occurrence of cold-induced abnormalities in myocardial perfusion and function in patients with scleroderma. The results suggest that cold exposure in such patients may elicit transient reflex coronary vasoconstriction resulting in reversible myocardial ischemia and dysfunction. Chronic recurrent episodes of coronary spasm may lead to focal myocardial fibrosis.

Primary Sjögren's syndrome in men:Clinical, serologic, and immunogenetic features

Although primary Sjögrens syndrome is a common rheumatic disorder in women, it is not well recognized in men. This study represents the first report of the clinical, serologic, and immunogenetic features of a group of 36 men with primary Sjögrens syndrome, which are contrasted with those of a group of 69 women with primary Sjögrens syndrome. The majority of male patients had extraglandular involvement including articular (78 percent), neurologic (39 percent), inflammatory vascular (25 percent), and lymphoproliferative disorders (17 percent). Although men were at the same risk for the development of extraglandular complications, there were significant serologic and immunogenetic differences. In sharp contrast to women with Sjögrens syndrome, men with Sjögrens syndrome were seronegative with respect to the presence of serum rheumatoid factor (p = 0.008) and antibodies to Ro(SS-A) (p = 0.016). The supertypic specificity, MT2 (DRw52), as in women, was strongly associated with primary Sjögrens syndrome in men when compared with race-matched control subjects (p = 0.0015). In men, however, the frequency of HLA-B8 and HLA-DR3, the most common DR locus specificity observed in women, was not statistically different from that observed in the normal control group.

Magnetic resonance imaging of cerebral lesions in patients with the Sjögren syndrome.

Thirty-eight patients with the primary Sjögren syndrome, 16 with active neuropsychiatric manifestations and 22 without clinical evidence of central nervous system involvement had magnetic resonance (MR) imaging. Eight patients had focal neurologic deficits (6 of these also had psychiatric, or cognitive dysfunction), and 8 had psychiatric or cognitive abnormalities alone. Magnetic resonance imaging showed abnormal results in 12 of 16 (75%; 95% CI, 48 to 93) patients with active central nervous system disease (67 focal lesions predominantly within the subcortical and periventricular white matter), and in 2 of 22 (9%; 95% CI, 1 to 29) patients without clinical evidence of central nervous system disease (P less than 0.0001). Seven of eight patients with focal neurologic deficits and 5 of 8 patients with psychiatric or cognitive dysfunction alone had abnormal results on MR imaging. Magnetic resonance imaging was more sensitive in the subgroup with focal deficits, (sensitivity, 88%; 95% CI, 44 to 97) than computerized axial tomography or cerebral angiography. Magnetic resonance imaging detects focal cerebral lesions in patients with the Sjögren syndrome and central nervous system involvement, including patients with psychiatric and cognitive dysfunction alone.

Aseptic meningoencephalitis in primary Sjogren's syndrome

The (clinical features and CSF characteristics of five patients with primary Sjogrens syndrome (SS) and associated aseptic meningoencephalitis (AME) are described. Episodes of AME were recurrent in four patients. Viral, fungal, and bacterial cultures were uniformly negative. Plasma cells were observed in the CSF but not in the blood of three patients. The CSF 1gG:albumin index was elevated, suggesting intrathecal synthesis of IgG in each of the four patients tested; each patient had either one or two broad bands with the mobility of IgG on CSF agarose electrophoresis. These observations are consistent with current understanding of SS as a polyclonal gammopathy associated with the multifocal proliferation of B lymphocytes and plasma cells.

Neuropsychiatric disease in Sjögren's syndrome: Anti-ribosomal P and anti-neuronal antibodies

PURPOSE Patients with Sjögrens syndrome (SS) may develop nonfocal (i.e., psychiatric and/or cognitive dysfunction) as well as focal, neuropsychiatric disease (CNS-SS). Anti-ribosomal P and anti-neuronal antibodies have been associated with nonfocal neuropsychiatric disease in systemic lupus erythematosus (SLE), particularly psychosis and depression. This study examines the spectrum of psychiatric and cognitive dysfunction observed in SS patients with focal, as well as nonfocal, central nervous system (CNS) disease and relates these observations to the presence of serum and cerebrospinal fluid (CSF) anti-ribosomal and anti-neuronal antibodies. PATIENTS AND METHODS One hundred thirty-one patients--patients with primary SS (n = 91), patients with secondary SS (n = 34), and mothers of infants with neonatal lupus erythematosus (NLE) (n = 6)--were studied. Patients were referred to a large tertiary referral center and the population was highly selected for CNS disease. Patients were evaluated clinically for focal and nonfocal CNS disease. Sera from 131 patients and 34 paired sera/CSF samples were examined by enzyme-linked immunosorbent assay and radioimmunoassay for the presence of anti-ribosomal P and anti-neuronal autoantibodies, respectively. Clinical features were categorized and autoantibody profiles obtained and correlated independently for statistical significance. Data were analyzed using the two-tailed Fisher exact test. RESULTS Psychiatric or cognitive impairment, usually mild or moderate, occurred in over 80% (63 of 77) of this highly selected population of SS patients, and more than 60% of patients (48 of 77) had both. Anti-ribosomal P antibodies occurred in six (4.6%) patients with SS and related disorders. None of the patients with primary SS had anti-ribosomal P antibodies, whereas they were present in a small number of patients with secondary SS (i.e., 4 of 34 [12%]) and in 2 of 6 mothers of infants with NLE. There was no correlation between nonfocal CNS disease, including psychosis or severe depression, and the presence of anti-ribosomal P antibodies. Paired serum CSF samples from 34 SS patients with active CNS disease, including 6 with psychosis and 5 with severe depression, did not contain either anti-ribosomal P or anti-neuronal antibodies. Anti-ribosomal P and anti-neuronal antibodies were present in a control subset of SLE patients defined serologically by the presence of anti-nDNA antibodies. CONCLUSION Patients with primary SS associated with CNS disease, including psychosis and depression, do not have serum or CSF autoantibodies to ribosomal P peptide or neuronal antigens, detected by binding to neuroblastoma cells. Thus, autoantibodies associated with nonfocal or diffuse CNS disease in classical SLE (particularly psychosis and depression) are not present in CNS-SS. The observations suggest that nonfocal CNS disease in CNS-SS and CNS-SLE may be mediated by different immunopathologic mechanisms. Potentially, these observations may have diagnostic and therapeutic implications in the management of patients with CNS-SS and patients with CNS-SLE.