Terumi Horiki

Combinations of HLA-DPB1 and HLA-DQB1 alleles determine susceptibility to early-onset myasthenia gravis in Japan

HLA class II alleles in the DQA1, DQB1, DRB1, and DPB1 genes were investigated in Japanese patients with myasthenia gravis (MG) by digestion of polymerase chain reaction amplified DNAs with allele specific restriction endonucleases (PCR-RFLP). A significantly higher frequency of DQB1*03, which includes *0301, *0302, *0303 and determines the serological DQ3 specificity, was observed in female patients less than 30 years in age at onset of disease compared with healthy controls (90.5 vs. 53.2%). This study also confirms the high incidence of DPB1*0201 in early-onset female patients compared to the controls (85.7 vs. 40.3%). Moreover, 81.0% of the early onset female patients were found to carry both DQB1*03 and DPB1*0201, compared to 17.7% of the controls. Since DQB1*03 and DPB1*0201 are not in linkage disequilibrium, both these alleles are supposed to be synergistically involved in disease development in early-onset female MG. In contrast, no obvious association of HLA-DQA1, DQB1, DRB1 and DPB1 alleles with either late-onset patients or patients with thymoma was observed. Clearly, the genetic background of Japanese females with early onset MG is different from that of other patients with MG.

Molecular markers of coagulation and fibrinolysis as indicators for the disease activity of rheumatoid arthritis

Pathological roles of coagulation and fibrinolytic system are suggested in the progressive and destructive articular lesions of rheumatoid arthritis (RA). In the present study, we simultaneously and serially determined recently available molecular markers of coagulation (thrombin-antithrombin III complex; TAT) and fibrinolysis/fibrinogenolysis [fibrin/fibrinogen degradation products (FDP),d-dimer and FDP-E], and compared their circulating levels with conventional indicators for the disease activity of RA in 31 patients. Either TAT,d-dimer or FDP-E levels well correlated with Lansbury activity index (LAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Compared with CRP levels, these hemostatic markers more strongly associated with LAI. In addition, the molecular marker levels correlated with each other in RA patients. The hemostatic markers were further determined on at least two different occasions in 14 RA patients. Percentage changes of thed-dimer level significantly associated with those of LAI, as observed between LAI and ESR or CRP levels. Our results clearly indicate excessive coagulation and fibrinolysis in active RA patients. Among the molecular markers determined,d-dimer was considered to be especially useful as a clinical indicator for disease activity of RA.

Clinical features of Sjögren’s syndrome associated with recurrent annular erythema

Our objective was to describe the clinical features of Sjögren’s syndrome (SS) with recurrent annular erythema which resembles subacute cutaneous lupus erythematosus (SCLE), and determine a possible association of anti-SS-A/Ro and/or SS-B/La antibody titers with the episodes of cutaneous manifestation. Recurrent annular erythema was observed in 4% (six patients; five females and one male) of our 143 patients diagnosed as primary SS. All the patients developed annular erythema on the facial area as their initial manifestation when they were between 21 and 31 years old. They had few subjective sicca symptoms, but both anti-SS-A/Ro and SS-B/La antibodies were positive and parotid sialography showed typical findings for SS (subclinical SS). Parotid gland swellings had developed in five of the patients during their follow-up periods, (3–12 years). In addition to the facial area, most patients repeated the cutaneous episodes on extremities and palmar, plantar or auricular areas. Skin biopsy was performed in three patients and the common findings were mononuclear cell infiltrations in the dermis with few epidermal changes. Transient leukopenia (four patients), low titers of anti-DNA antibodies (one patient) and chronic false-positive results of serological tests for syphilis (one patient) were observed. Two of our patients, therefore, temporarily fulfilled four items of the ARA classification criteria for systemic lupus erythematosus (SLE), if their facial erythema was considered as malar rash. Serum antibodies to 52 kDa SS-A/Ro peptides (80%) were more frequently detected in the five patients examined by enzyme-linked immunosorbent assays (ELISA), compared with those to 60 kDa SS-A/Ro peptides (40%). Furthermore, we could serially determine serum anti-SS-A/Ro and SS-B/La antibody titers in three patients by using ELISA for 3 or 4 years. Annular erythema usually developed when the antibody titers became relatively high and disappeared after the treatment with oral prednisolone which suppressed the antibody titers. We could observe five pregnancies in our three patients and all the patients developed annular erythema during their pregnant periods. Their five infants, however, were free from any complications such as neonatal lupus erythematosus and congenital heart block. We conclude that annular erythema is a rare manifestation of SS and develops in relatively young patients who are subclinical for sicca symptoms. The cutaneous episodes seemed to relate with anti-SS-A/Ro and/or SS-B/La antibody titers. Some of the erythema observed in SS patients may belong to SCLE, but they do not usually develop typical SLE. The possibility that SS may be more frequent in the SCLE patients remains to be determined.

Spontaneous and anti-Fas antibody-mediated apoptosis of the peripheral blood lymphocytes in Sjögren’s syndrome, rheumatoid arthritis and systemic lupus erythematosus

The objective of this study was to clarify possible roles of lymphocyte apoptosis in autoimmune rheumatic diseases. Spontaneous and anti-Fas antibody-mediated apoptosis of peripheral blood (PB) lymphocytes were measured by a flow cytometric method using propidium iodide in primary Sjögren’s syndrome (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Spontaneous apoptosis levels were significantly higher in 26 SLE patients than in 19 healthy controls. The apoptosis levels were not significantly different between 19 primary SS patients or 28 RA patients and the controls, but high apoptosis levels were observed in some of the patients. The apoptosis of PB lymphocytes was also enhanced in seven SS patients with RA and 16 SS patients with SLE. Anti-Fas antibody could induce apoptosis of PB lymphocytes from both healthy controls and patients’ groups. The antibody-mediated apoptosis levels were higher in RA, SLE and secondary SS patients with RA or SLE, but not in primary SS patients. Each patients’ group was further divided into two groups according to their mean apoptosis levels: patients with high and those with low spontaneous or antibody-mediated apoptosis levels. Clinical variables reflecting disease activity for each disease were then compared between the two groups. Serum rheumatoid factor (RF) and anti-SS-A/Ro antibody titers were higher in the RA or primary SS patients with high spontaneous apoptosis levels than those with low apoptosis levels, respectively. When all the patients’ groups were evaluated together, the spontaneous apoptosis levels negatively correlated with PB lymphocyte counts. In addition, the spontaneous apoptosis levels were decreased by the co-culture of PB lymphocytes with interleukin-2 (IL-2: 100 U/ml) in most individuals including patients and healthy controls. We conclude that spontaneous apoptosis of PB lymphocytes was enhanced in SLE and secondary SS patients. Production of RF or anti-SS-A/Ro antibodies was associated with enhanced apoptosis of PB lymphocytes in RA or primary SS patients. The apoptosis levels were related with lymphocytopenia observed in the patients examined, although various factors including IL-2 seemed to be protective against the apoptosis of circulating lymphocytes. Furthermore, anti-Fas antibody induced apoptosis of PB lymphocytes from the healthy controls and patients, and the antibody-mediated apoptosis levels were high in RA, SLE and secondary SS patients.

A case of systemic lupus erythematosus with various central and peripheral neurological disorders developed with motor paralytic bladder as a major manifestation

A 29-year-old female with systemic lupus erythematosus who developed accerelated hypertension, motor paralytic bladder and various other neurological abnormalities is described. Cystometry demonstrated flaccid atonic neuropathic bladder. Elevated protein level and albuminocytologic dissociation were recognized in her cerebral spinal fluid. Magnetic resonance imaging study detected high signal intensities in themedulla oblongata andcauda equina. Her clinical symptoms and laboratory abnormalities were resolved after two courses of methyl-prednisolone pulse therapy. Possible roles of antiphospholipid antibodies were considered in the pathogenesis of her neurologic abnormalities.