A soluble acidic protein of the cell nucleus which reacts with serum from patients with systemic lupus erythermatosus and Sjögren's syndrome.

A soluble nuclear antigen that reacts with sera obtained from patients with systemic lupus erythematosus and Sjögren's syndrome has been described. The antigen, tentatively named the Ha antigen after the prototype serum, was shown to react with specific antibodies by precipitin, complement fixation, and immunofluorescence techniques. The Ha antigen prepared from isolated nuclei of calf thymus glands, calf liver, and rat liver showed identical immunological reactivities; a wide distribution among different species and tissues is presumed. The Ha antigen was destroyed by trypsin and relatively mild heat or pH variation from neutrality, but was resistant to DNase or RNase. Many of these characteristics are similar to those of the "B" antigen to which antibodies have recently been described in Sjögren's syndrome. The nuclear origin of the Ha antigen was confirmed by the speckled nuclear immunofluorescence staining pattern given by purified antibody to Ha obtained from a specific immune precipitate. Preliminary results showed approximately 13% of patients with systemic lupus erythematosus and 30% of patients with Sjögren's syndrome had precipitating antibodies to the Ha antigen.

Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositis-scleroderma overlap.

Autoantibodies in the serum from a patient with connective tissue disease have been used to define a high molecule weight acidic nuclear protein antigen. The antigen tentatively termed Ku, after the first two letters of patient's name, has distinct physicochemical properties and immunological specificities that distinguish it from previously reported antigens. The Ku antigen has an apparent 300,000 mol wt as determined by gel filtration and sucrose density gradient ultracentrifugation techniques. The antigen is destroyed by trypsin, mild heating, and pH variations greater than 10 and less than 5. Treatment with ribonuclease or deoxyribonuclease did not affect the antigenic reactivity. The Ku antigen was demonstrated in the soluble extracts of human, calf, and rabbit, but not of rat tissues. Purified antibody localized the Ku antigen within the nuclei of human liver where a "reticular" pattern of immunofluorescence was seen. Of 330 patients with various connective tissue diseases, 9 had precipitating antibodies to the Ku antigen. Preliminary results of clinical analysis indicated that antibody to the Ku antigen might become a useful marker for a group of patients with clinical characteristics of both polymyositis and scleroderma with a good prognosis.

Demonstration of antibodies to soluble nuclear antigens by complement fixation test. An application of microtiter technique.

The complement fixation test utilizing the microtiter system was applied to study sera from patients with a variety of connective tissue diseases for the presence of antibodies to soluble nuclear antigens. A good correlation was found between microtiter complement fixation and hemagglutination for anti-RNP and anti-Sm antibodies. Anti-Ha antibodies were detected by complement fixation but not by hemagglutination. Different enzyme digestions of the soluble nuclear antigen prior to assay and use of a quantitative microcomplement fixation test were found to improve the analysis of sera with multiple antibodies.

Restricted heterogeneity and changing spectrotypes in autoantibodies to La/SS-B.

Isoelectric focusing (IEF) spectrotype of specific immunoglobulins has been studied as a marker for B-cell clonality. In the present study, the spectrotype of anti-La antibodies in human autoimmune sera were analyzed by newly developed IEF sandwich assay in which focused total immunoglobulin on filter papers are incubated with crude antigen followed by horse-radish peroxidase-labeled anti-La antibodies. The anti-La spectrotypes contained oligoclonal bands, the positions and patterns of which are different in each patient, suggesting the preferential expansion of limited numbers of anti-La producing B-cell clones unique to individual patients. Furthermore, the bands on anti-La spectrotype in sequentially obtained sera changed continuously, suggesting alteration in the expanding anti-La producing clones. These may reflect affinity maturation and/or diversification of the B-cell epitopes involving somatic mutation.

Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the dissociation of the drug.

We aimed to clarify the relationship between drug dissociation (sulphisomidine) and its direct transport from the nasal cavity to the cerebrospinal fluid (CSF). Rat nasal cavities were perfused in a single pass system with buffers (pH 5.5, 6.5, 7.4, 8.7 and 9.4). Plasma and CSF were collected and the concentration of sulphisomidine was measured. Nasal clearance increased with the increase in the un-ionized fraction of the drug. The ratio of the drug concentration in CSF to that in the nasal perfusion fluid (the index of the degree of the drug transport from the nasal cavity to CSF), was changed in accordance with the un-ionized fraction of drug. These results show that both the nasal absorption and the drug transport conform to the pH partition theory.

Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity.

The aim of the present study has been to confirm the existence of a transport pathway for a drug (cephalexin) to the cerebrospinal fluid (CSF) directly from the nasal cavity, by comparing the drug's concentrations in CSF after intranasal (i.n.), intravenous (i.v.) and intraduodenal (i.d.) administration. Higher levels of the drug were found in CSF following i.n. administration compared with the i.v. and i.d. routes, even though its plasma concentrations were similar. These findings suggest the existence of a direct transport pathway for cephalexin from the nasal cavity to the CSF. The concentration of drug in CSF at 15 min after i.n. administration was higher than that at 30 min. In contrast, its concentrations in CSF at 15 min after i.v. and i.d. administration were not significantly different from those at 30 min. The results confirm the presence of a direct transport pathway to CSF from the nasal cavity. This pathway may represent a new delivery route to CSF and possibly to brain parenchyma.

Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the molecular weight of drugs.

To clarify the relationship between the direct transport from the rat nasal cavity to the cerebrospinal fluid (CSF) and the molecular weight of the drug, the transport of fluorescein isothiocyanate-labelled dextran (FD) with various molecular weights was investigated. FDs (average molecular weights 4,400 (FD4); 9,400 (FD10); 18,900 (FD20); 40,500 Da (FD40)) were administered nasally or intravenously to rats, and the concentrations in the plasma and the CSF were measured and compared. None of the FDs were detected in the CSF after intravenous administration. However, FD4, FD10 and FD20 were observed to appear in the CSF after nasal administration, whereas the concentration in the plasma was much lower than that after intravenous administration. FD40 was not detected even after nasal administration. In addition, the concentration of these FDs in the CSF decreased with the increase in the molecular weight of FDs. These findings show that drugs with a molecular weight up to at least 20,000 Da can be directly transported from the nasal cavity to the CSF and that the transport of FDs to the CSF is dependent on their molecular weights.

Chronic destructive monoarthritis of the wrist in patients with anti-SSA/Ro antibodies: report of two cases.

Among 340 patients with rheumatic diseases, two cases of chronic destructive monoarthritis of the wrist with anti-SSA/Ro antibodies and rheumatoid factor, were observed for over three years. It is not clear whether these cases represent a specific subset of rheumatoid arthritis (RA) or whether they may progress to diffuse symmetrical destructive polyarthritis typical of RA. Long-term follow-up studies including analysis of autoantibodies will be needed to clarify the characteristics and course of chronic monoarthritis.

Systemic lupus erythmatosus associated with autoimmune hepatitis two cases with novel autoantibodies to transfer RNA-related antigens.

Two cases of systemic lupus erythematosus (SLE) with autoimmune hepatitis are reported. Both patients had a mild form of SLE without central nervous system or renal involvement and showed a rapid response to corticosteroid therapy. Neither of them had antibodies to mitochondria, smooth muscle, and liver/kidney microsome-1 related to autoimmune hepatitis. Instead, novel autoantibodies which react with transfer RNA-related antigen were detected. These autoantibodies could be a useful marker for classification of SLE associated with autoimmune hepatitis.

Pyloric stenosis in a patient with progressive systemic sclerosis.

A 64-year-old Japanese woman with progressive systemic sclerosis (PSS) who developed severe pyloric stenosis is described. The conservative treatments brought only the temporary symptomatic relief, and pyloroplasty became necessary. No ulcerative lesions or tumors were found in the resected stomach or duodenum specimens implicated for stenosis. The histological examinations revealed edema and replacement fibrosis in the pyloric ring. The possible mechanisms of pyloric stenosis are discussed.

A case of Sjögren's syndrome complicating immune-mediated aplastic anaemia.

A 78-year-old Japanese woman with Sjögren's syndrome complicating immune-mediated aplastic anaemia is described. A diagnosis of aplastic anaemia was made from severe pancytopenia with hypoplastic marrow. Laboratory studies suggested an association of bone marrow suppressive T-lymphocytes with the pathogenesis of aplastic anaemia. Following the administration of mepithiostan and prednisolone, pancytopenia improved gradually. Two years after the onset of aplastic anaemia, Raynaud's phenomenon developed and examinations revealed the existence of keratoconjunctivitis sicca and anti-SSA/Ro and anti-SSB/La antibodies.

Rheumatoid arthritis in a patient with pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a rare, inherited disorder of the connective tissue. Possible association of autoimmune thyroiditis and PXE has been suggested, but reports of other autoimmune diseases complicating PXE are rare. We report a case of rheumatoid arthritis (RA) in a patient with PXE. Since the frequency of PXE is likely to be underdiagnosed, further studies to elucidate the true incidence and significance of the association of RA and PXE will be needed.

[Quality of life, subjective health status and health and life satisfaction in rheumatoid arthritis].

A Japanese version of Arthritis Impact Measurement Scales (AIMS) was developed after the original AIMS Version 2 and utilized for Quality of Life (QOL) measurement in 691 patients with Rheumatoid Arthritis (RA). Various medical (physical and laboratory) examinations, which are widely used in the clinical settings for the assessment of RA activity and severity, were also performed by physicians. Interrelationships between QOL, patient subjective health status, and health and life satisfaction were analyzed with the following results: 1: The effect of QOL impairment by RA upon patients' subjective health rating and health satisfaction were not constant over the range of severity of disease status. Pain was found to lower overall subjective health and health satisfaction regardless of RA class. On the other hand, while the deterioration of mobility aspects of QOL had negative effects upon patients' subjective health status and satisfaction among less-disabled RA patients, any of physical aspects of QOL, including the degree of mobility impairment, showed no significant association with patients' subjective health status and satisfaction in the more disabled. 2: Psychological aspects of QOL (mood and tension) had significant associations with patients' subjective health status and satisfaction. In the less severe group, mood impairment had a significant effect on subjective health and satisfaction, while in the more severe group tension showed a significant association. It was indicated that management of psychological aspects of QOL is important in RA patients to improve and advance their subjective health status and satisfaction. 3: Although social aspects of QOL, i.e. social support, social life and job status, showed no significant relationship to subjective health rating and health satisfaction, those with less disease severity who lacked social support and who had a jobless state were likely to have lower disease acceptance and life satisfaction, while those with more severe disease who had less social interaction manifested lower life satisfaction. These results suggested that social aspects of QOL, while not directly associated with subjective health rating, could be important factors affecting disease acceptance and life satisfaction.

[Frequency of anti-centromere antibodies in the anti-mitochondrial antibody positive sera].

Autoantibodies give us useful informations for the understanding of the co-existence of multiple autoimmune diseases in an individual patient. This study was undertaken to clarify the frequency of anti-centromere antibodies in the sera which were positive for anti-mitochondrial antibodies. Serum samples with anti-mitochondrial antibodies were examined on the frozen rat liver section and HEp-2 cells by indirect immunofluorescence. 57 out of 239 anti-mitochondrial antibody positive sera were found to contain specific autoantibodies reactive with centromeric antigens of the HEp-2 chromosomal spreads. The co-existence of anticentromere antibodies with anti-mitochondrial antibodies were significantly more frequent than with other defined autoantibodies. Clinical observation which shows frequent association of CREST syndrome and primary biliary cirrhosis appear to be explained by the frequent occurrence of anti-centromere antibodies and anti-mitochondrial antibodies.

[Granulocytic sarcoma presenting as an epidural mass with spinal cord compression].

A 73-year-old man was admitted because of back pain and paralysis of the lower extremities. Magnetic resonance imaging of the spine at the Th4-6 level, obtained after gadolinium injection, demonstrated abnormal signal intensity within the Th5-6 vertebral bodies and an extradural soft-tissue mass on the right posterior side of the spinal canal, compressing the thecal sac. The patient underwent prompt decompression with laminectomy, but this was unsuccessful. A biopsy sample of the mass revealed the histological features of granulocytic sarcoma, including diffuse infiltration of numerous cells containing cytoplasmic granules and immunohistochemical positivity for myeloperoxidase. Two months later, a subcutaneous soft-tissue mass appeared at the anterior chest wall, and this was confirmed to be granulocytic sarcoma by microscopic examination. Both of these tumors were radiosensitive, but the patient died of septic shock. Granulocytic sarcoma usually occurs in association with leukemia or other myeloproliferative disorders. However, it is rarely found before leukemia becomes evident in the peripheral blood or bone marrow; only eight such instances have been reported previously.

[Efficacy of beraprost sodium on Raynaud's phenomenon in patients with systemic sclerosis].

Raynaud's phenomenon is an important clinical manifestation in patients with systemic sclerosis (SSc). No effective therapy, however, has been established for this phenomenon. Beraprost sodium, a stable prostacycline (PGI2) analogue, has been reported to improve hemorrheological impairment in patients with rheumatic diseases. In this study, we, therefore, examined the efficacy of beraprost sodium on Raynaud's phenomenon in 30 patients with SSc. Sixty micrograms per day of beraprost sodium was found to be effective in 14 patients (47%) in the period of 15.0 +/- 12.5 weeks. Raynaud's phenomenon in patients who responded to beraprost sodium was characterized by infrequent nail fold thrombosis and narrower hand areas affected by Raynaud's phenomenon, with mild secondary symptoms such as pain. These results indicate that beraprost sodium is effective for mild forms of Raynaud's phenomenon in patients with SSc.

[A case of systemic lupus erythematosus associated with spinal epidural hematoma].

A 47 year-old Japanese female who showed transverse myelopathy (TM) due to spinal epidural hematoma diagnosed by MRI in the course of systemic lupus erythematosus (SLE) was reported. She was admitted to Keio University Hospital due to paraplegia, anesthesia of lower extremity, urinary disturbance. Neurological examination revealed transverse disturbance of Th 10. Lumbar spinal cord MRI showed irregular mass that located at epidural region of 9th-11th thoracic vertebrae. When the laminectomy of 9th-11th thoracic vertebrae was performed, hematoma (4.5 cm x 1.5 cm in size) was confirmed and removed completely. Post operative condition was stable and symptoms had been improving gradually. It has been reported that TM associated with SLE was closely related to myelitis. In this case, epidural hematoma was a major cause of TM and MRI was very useful for her diagnosis and treatment. This is the rare case of SLE associated with spinal epidural hematoma and was thought as a important case to consider the cause of neurological complication of SLE.

[A case of adult onset Still's disease complicated with adult respiratory distress syndrome and disseminated intravascular coagulation].

A 71 year-old man with adult onset Still's disease was admitted to our hospital because of fever, sore throat, myalgia and macular nonpruritic salmon pink eruption. He was treated with prednisolone, 40 mg daily and these symptoms disappeared. When the dose of prednisolone was reduced to 30 mg daily, he began to notice fever. 5 days later he developed adult respiratory distress syndrome (ARDS). The dose of prednisolone was increased to 50 mg daily and oxygen administration was started. All symptoms began to improve immediately and the dose of prednisolone was decreased to 40 mg daily. 10 days later he noticed fever and skin rash. Laboratory investigation showed platelet counts of 69,000/mm3, a ferritin of 37,000 ng/ml, and increased fibrinogen degradation product, indicating increased activity of adult onset Still's disease associated with disseminated intravascular coagulation (DIC). The dose of prednisolone was again increased to 60 mg daily, and 100 mg of nafamostat mesilate was administrated intravenously. All above symptoms associated with adult onset Still's disease and DIC disappeared. The dose of prednisolone was gradually decreased and the clinical course was uneventful with daily administration of 10 mg of prednisolone. Although there are a couple of case report which described the association of adult onset Still's disease with either ARDS or DIC, the association of adult onset Still's disease with both ARDS and DIC have not been reported yet.

[An adult case of dermatomyositis complicated with cecum perforation and panniculitis].

The case of dermatomyositis complicated with cecum perforation and panniculitis occurred in a 62-year-old woman was reported. She was admitted to Keio University Hospital with a history of proximal muscular weakness, and dysphagia. Physical examination showed erythema over the face and shoulder. Serum level of muscle enzymes was remarkably increased. The diagnosis of dermatomyositis was made based on proximal muscular weakness, elevated serum level of muscle enzymes and myogenic change of electromyocardiogram. The treatment with 60 mg/day of prednisolone was started, and was a good response. However, 7 months later the disease became active again when the amount of prednisolone was reduced to 13 mg/day. Subsequently she complained of abdominal pain on the right lower quadrant. The surgical findings included peritonitis due to the perforation of the cecum and multiple ulcers of the cecum. After operation, azathioprine was added. Four years and 9 months later, she noticed skin erythema with ulceration and subcutaneous nodule. Skin biopsy indicated the findings of the panniculitis with membrano-cystic lesion. It was thought that both cecum perforation and panniculitis were caused by angiopathy which was often seen in childhood dermatomyositis.

Autoantibodies to the Sm antigen: immunological approach to clinical aspects of systemic lupus erythematosus.

The precise antigenic peptide of Sm antigen (U small nuclear ribonucleoproteins, U snRNP) and the clinical significance of anti-Sm antibodies in systemic lupus erythematosus (SLE) detected by a sensitive radioimmunoassay were studied. By immunoblotting, anti-Sm sera reacted with B'/B peptides of U1 snRNP and D peptide of U1-U2 snRNP, while anti-U1 RNP recognized 68k, A, B'/B and C peptides. Reblotting study using the specific antibodies against each peptide eluted from the blot sheets demonstrated that B'/B and D peptides shared a common Sm antigenic epitope. We purified D peptide from U1 snRNP and established a radioimmunoassay. Anti-Sm antibodies were found in 30% of the patients with SLE using this method, which was more sensitive than the conventional assays. Anti-Sm was associated with late onset renal disease and poor prognosis when analyzed with Cox's regression model.