[Autoimmune cholangitis (AIC) associated with myositis in monozygotic twins].

A 53-year-old female suffered from joint pain and muscle weakness in all extremities in 1991. Laboratory data showed increased creatine phosphokinase (CK) and aldolase. Liver dysfunction and weakness of proximal muscles also appeared and polymyositis (PM) was suspected. Two years later, she was diagnosed with dermatomyositis (DM) through skin and muscle biopsy. Because elevation of biliary enzymes and transaminases were continued, liver biopsy was performed in 1997. Histopathological findings of her liver were compatible with primary biliary cirrhosis (PBC). Similar conditions were noticed in her identical twin as well. DM associated with PBC is unusual and cases of monozygotic twins with both conditions are very rare. The difference between PBC and autoimmune cholangitis (AIC) which has recently reported and the genetic influence on the pathogenesis of DM and AIC are also discussed.

IgA class anti-beta2-glycoprotein I in patients with systemic lupus erythematosus.

OBJECTIVE: To search for a possible relationship between the presence of IgA class anti-beta2-glycoprotein I antibody (abeta2-GPI) and clinical manifestations, including thrombotic episodes, in patients with systemic lupus erythematosus (SLE). METHODS: Serum IgA abeta2-GPI levels in 124 Japanese patients with SLE were measured using a phospholipid independent enzyme immunoassay. Relationships to clinical histories and to various laboratory data including IgG and IgM class abeta2-GPI were examined. RESULTS: Twenty-five percent of patients with SLE were positive for IgA abeta2-GPI. Patients with a history of thrombosis had significantly higher probabilities for positivity of IgA abeta2-GPI, compared to those without. The presence of IgA abeta2-GPI was correlated with presence of lupus anticoagulant and/or biological false positive result for serological syphilis test. Titer of IgA abeta2-GPI significantly correlated with values of IgG abeta2-GPI, IgM abeta2-GPI, and anti-DNA antibodies. CONCLUSION: The presence of IgA abeta2-GPI may be related to the occurrence of thrombosis in patients with SLE. Measurements of IgA abeta2-GPI may be of value for evaluating risk of thrombosis in patients with SLE.

Z-100, extracted from Mycobacterium tuberculosis strain Aoyama B, inhibits the development of collagen-induced arthritis in mice.

We evaluated the effects of Z-100, extracted from human type Mycobacterium tuberculosis strain Aoyama B, on collagen-induced arthritis (CIA) in mice. One hundred thirty-five DBA/1J mice, 8 weeks of age, were assigned to 9 groups and immunized with bovine type II collagen (CII) or CFA. From the next day, Z-100 at doses of 0.004, 0.04, or 0.4 mg/kg B.W./d for 48 d was intradermally injected into the tail base. Methotrexate (MTX) at daily doses of 0.1, 0.3, or 1.0 mg/kg B.W. and cyclophosphamide (CY) at a daily dose of 5 mg/kg B.W. were used as reference drugs. The effects of these drugs on CIA mice were evaluated in terms of the incidence of CIA, the arthritis index (AI), and hind paw edema, after which the animals were sacrificed at 49 d, and both anti-CII antibody titer and delayed-type hypersensitivity (DTH) reaction were measured. In the arthritic control groups, the AI and hind paw edema were significantly increased after the second immunization on day 28. The anti-CII antibody titer and DTH reaction were significantly increased compared to normal mice on day 49. Z-100 significantly inhibited the AI at a dose of 0.4 mg/kg/d on day 49, and suppressed the incidence of both CIA and hind paw edema. Increases in both anti-CII antibody titer and DTH reaction in CIA mice were prevented by treatment with Z-100 at 0.4 mg/kg/d. MTX, in a dose-dependent manner, and CY, at a dose of 5 mg/kg/d, inhibited the incidence of CIA, AI, hind paw edema, anti-CII antibody titer and DTH reaction in CIA mice. Z-100 at a dose of 0.4 mg/kg was as effective as MTX was at a dose of 0.3 mg/kg against the DTH reaction, and it had no side effects. These results suggest the usefulness of Z-100 in patients with chronic rheumatoid arthritis.

Lupus erythematosus profundus around the salivary glands: a case resembling submandibular salivary gland disease.

In a 29 year old Japanese woman with SLE, a bilateral submandibular mass was detected. Computed tomographic (CT) scan suggested inflammatory changes around the submandibular glands. Histological findings of the deep skin biopsy showed typical changes of lupus erythematosus profundus (LEP). LEP should be considered in the differential diagnosis of an unexplained submandibular mass in a subject with SLE.

Serum levels of soluble Fas/APO-1 (CD95) and its molecular structure in patients with systemic lupus erythematosus (SLE) and other autoimmune diseases.

There are two major forms of the Fas molecule, membranous Fas and soluble Fas (sFas). To clarify the clinical significance of sFas in autoimmune diseases, we designed a sandwich ELISA to determine serum concentrations of sFas and its molecular structure, and we then analysed the correlation between levels of sFas and laboratory findings in patients with SLE and other autoimmune diseases. The levels of serum sFas were significantly higher in SLE patients than in subjects with other autoimmune diseases and in healthy donors, and the frequency of a positive serum sFas was much greater in SLE patients with high SLE disease activity index scores than in those with low scores. In addition, sFas-positive SLE patients showed a significant difference in various laboratory parameters from sFas-negative SLE patients. Serial measurements of serum sFas levels in SLE patients with active disease revealed that the elevated level of sFas dramatically decreased with improvement in clinical and laboratory findings, following corticosteroid therapy. We propose that the serum level of sFas can serve as an appropriate marker for evaluating SLE disease activity. Serum sFas is heterogeneous with respect to molecular structure, thus several mechanisms are involved in the generation of sFas.

Epidemiological analysis of prognosis of 496 Japanese patients with progressive systemic sclerosis (SSc). Scleroderma Research Committee Japan.

For the first time, we performed an epidemiological study of SSc in Japan to study the factors influencing prognosis, survival rate and cause of death of Japanese SSc patients and to compare our data with those from foreign countries. Prognosis of 496 Japanese patients with progressive systemic sclerosis (SSc) was analyzed based on clinical data described in case cards provided by the members of the Scleroderma Research Committee of the Japanese Ministry of Health and Welfare. The essential observation period was from 5 to 20 years, at ending in 1994. Ninety patients died (males 11, females 79). The age of onset of the deceased patients was significantly higher than that of surviving patients (deceased, 45.6 yrs, surviving 41.3 yrs). Statistically significant factors for a poor prognosis were as follows: Barnett type III > type II > type I, positive for anti-Scl-70 antibody, negative for anti-centromere antibody. The survival rate at 5 years after the onset of the disease was 0.937, followed by 0.82 at 10 years, 0.567 at 20 years and 0.40 at 30 years after the onset. Sex was not a predictor for prognosis, although male patients died at an earlier stage of the disease. The most common causes of death were heart failure, pulmonary insufficiency, lung fibrosis, and renal failure. Twenty-four patients had cancer of which 13 were lung cancers. The current status of the survival rate and prognostic factors of 496 Japanese SSc patients is summarized. In future, more well-controlled studies using the same criteria should be performed for the better understanding and management of SSc.

Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate whether anticardiolipin antibodies (aCL) in patients with systemic lupus erythematosus (SLE) bind to beta 2-glycoprotein I (beta 2GPI), and to search for a relationship between the presence of IgG and/or IgM anti-beta 2GPI antibody and clinical manifestations in SLE patients. METHODS: IgG and IgM anti-beta 2GPI in 308 Japanese SLE patients were measured using phospholipid-independent enzyme immunoassays. Relationships to clinical histories and to various laboratory data were examined. RESULTS: The values of anti-beta 2GPI and aCL, as measured by conventional enzyme immunoassay, showed a strong correlation, but the anti-beta 2GPI assay was more useful in distinguishing beta 2GPI-dependent aCL from beta 2GPI-independent aCL. The presence of IgG anti-beta 2GPI was associated with an increased frequency of a history of thrombosis. Comparisons of various laboratory data suggested that the titer of anti-beta 2GPI may fluctuate with disease activity. CONCLUSION: The results suggest that pathogenic aCL is directed against structurally altered beta 2GPI and that enzyme immunoassay for anti-beta 2GPI may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE.

[A case of melorheostosis with linear sclerodermatous skin changes].

A 69-years old Japanese woman complained of pain in the left elbow joint and thickened skin over the left upper limb. The pain had been present for 20 years, and the thickened area of the skin gradually enlarged during this period. Her left elbow joint showed some limitation of motion. There was no record of any similar condition in her family history. Radiographs of the left limb showed cortical hyperostosis extending from the middle of the left humerus to the distal end of the radius. Radiographs of the other limbs were normal. A technetium 99m-methylene diphosphonate bone scintigraphy revealed increased uptake in the areas of radiographic hyperostosis. The diagnosis of melorheostosis was made. Skin biopsy of thickened area was performed. The epidermis was normal, and proliferation of normal-appearing collagen fibers into the subcutaneous fat was noted. No inflammatory changes were found. The cause of sclerodermatous skin changes was thought to be not by linear scleroderma but by melorheostosis. In cases of linear sclerodermatous changes, melorheostosis as its origin should be considered.

[The association of the disease activity of rheumatoid factor positive vasculitis and the level of rheumatoid factor].

Rheumatoid factor (RF), an autoantibody against the Fc portion of denatured IgG, has long been recognized as an important biologic marker not only for rheumatoid arthritis but also for other auto-immune diseases. In this study, we measured the level of serum RF in four patients with RF positive systemic vasculitis using laser nephelometry. Three patients were diagnosed as polyarteritis nodosa and the other patient was diagnosed as systemic vasculitis without the finding of typical necrotizing vasculitis from biopsies. In the result, we found that the level of RF paralleled the disease activity in these cases. When active phase of the disease, the level of RF showed very high, and after the treatment combined with plasmapheresis, corticosteroid and immunosuppressive agent, the level of RF decreased in accordance with CRP, ESR and clinical features. These suggested that RF was the disease specific marker for RF positive vasculitis and beneficial informations for proper diagnosis and better treatment could be provided by measurement of the level of RF in patients with RF positive systemic vasculitis.

[A case of mixed connective tissue disease with acute interstitial pneumonitis].

A 43-years-old woman was admitted to the Hokkaido University Hospital because of high fever, muscle weakness and dyspnea in May 1993. She had has muscle weakness of upper extremities since December 1992. She had developed swollen hand, polyarthralgia and Raynaud's phenomenon. High fever and severe dyspnea developed in May 1993. Chest roentogenogram was normal in April 1993. Physical examination showed Velcro rales in both lower lung fields. Her laboratory data showed increased muscle enzymes, high titers of anti-nuclear-antibody (1: 1280) and anti-RNP-antibody (index 199.4 (normal < 7)). Anti-DNA, anti-Sm and anti-Jo-1-antibodies were all negative. Blood gas analysis showed severe hypoxemia. Chest roentogenogram revealed diffuse bilateral interstitial infiltrates prominent in the bases. Diagnosis of mixed connective tissue disease with acute interstitial pneumonitis was made. She was treated with steroid pulse therapy (methylprednisolone 1 g x 3 days) followed by high dose oral prednisolone (60 mg/day), and diffuse interstitial infiltrates disappeared within one week. Prednisolone could be tapered to 17.5 mg/day without relapse. Acute interstitial pneumonitis is a rare complication of mixed connective tissue disease, but may be life threatening. In such cases, high dose steroid therapy should be started without delay.

Severe hepatic involvement without inflammatory changes in systemic lupus erythematosus: report of two cases and review of the literature.

Hepatic diseases in systemic lupus erythematosus (SLE) are not rare, but liver biopsies of those cases are usually reported as chronic hepatitis or steroid-induced steatosis. We describe two unusual patients with active SLE who displayed liver dysfunction without inflammatory changes or associated with drug administration. A liver biopsy in case 1 showed massive hepatic cell damage resulting in acute hepatic failure. In case 2, the liver specimen revealed diffuse fatty degeneration without symptoms specific to liver dysfunction. No inflammatory cell infiltrate was observed in the liver tissue of either patient. After steroid pulse therapy (case 1) and the administration of 60 mg/day of prednisolone (case 2), liver function improved in parallel with the stabilization of the other manifestations of SLE. No other causes for liver damage except for SLE were observed in either case. Therefore it is supposed that the liver impairments in these cases were one manifestation of SLE.

Up-regulated expression of Fas antigen (CD95) by peripheral naive and memory T cell subsets in patients with systemic lupus erythematosus (SLE): a possible mechanism for lymphopenia.

Fas antigen (CD95) is a membrane-associated molecule that mediates apoptotic cell death and may play a role in the induction and maintenance of T cell tolerance. To elucidate the involvement of Fas antigen in human autoimmune diseases, we analysed Fas antigen expression by peripheral T cells from patients with SLE and rheumatoid arthritis (RA), using three-colour flow cytometry. Both CD4+ and CD8+ T cells from SLE patients expressed Fas antigen in a higher density than did these cells from healthy donors and from RA patients. Enhancement of Fas antigen density was noted in Fas+CD45RO+ memory T cells from SLE patients. More remarkably, a significant expression of Fas antigen was observed in CD45RO- naive T cells from SLE patients. CD4+CD45RO- T cells from SLE patients co-expressed Fas antigen and early to intermediate activation antigens such as CD25 and CD71, and late activation antigen HLA-DR in only FashiCD4+ naive T cells. Such up-regulation of Fas antigen expression in SLE patients seems to be clinically meaningful, because mean fluorescence intensity (MFI) of Fas antigen on CD4+ T cell subsets inversely correlates with the absolute size of CD4+ T cell subsets in peripheral blood of SLE patients. These results suggest that T cells with increased Fas antigen expression may be highly susceptible to apoptotic cell death, in vivo. A putative mechanism for lymphopenia in SLE patients is discussed.

Immunogenetics of epitopes of the carboxyl terminus of the human 60-kD Ro autoantigen.

Systemic lupus erythematosus is associated with the presence of autoantibodies which bind several ribonucleoproteins, including Ro (or SS-A). We have explored the relationship of the HLA-DQ and T cell receptor alleles in patients producing autoantibodies binding the 13-kD carboxyl terminus fragment of the 60-kD Ro and with autoantibodies binding a peptide epitope within this fragment (amino acid residues 480-494). Antibodies binding the 13-kD fragment are more likely to be found in the sera of patients with particular DQA1 and DQB1 alleles, while antibodies binding the epitope at 480-494 are found almost exclusively in the sera of patients with a Bg/II 9.8-kb polymorphism of the T cell receptor beta gene. Meanwhile, in these same patient sera the level of autoantibodies binding the complete 60-kD Ro particle is associated with a distinct pattern of alleles at these same immunoregulatory loci. These data demonstrate that component parts of autoantibody responses may be under genetic control which can be distinguished from the HLA associations characteristic of the response to the intact, complete autoantigen.

A case of Crow-Fukase syndrome with elevated soluble interleukin-6 receptor in cerebrospinal fluid. Response to double-filtration plasmapheresis and corticosteroids.

We report the case of a 33-year-old Japanese male who presented with thrombocytosis, lower limb edema, severe polyneuropathy with elevated cerebrospinal fluid (CSF) protein level and serum IgA lambda monoclonal component, fulfilling the manifestations of Crow-Fukase syndrome. A high level of soluble interleukin-6 receptor in the CSF was also found, which fluctuated in parallel with the clinical course. Initial treatment with double-filtration plasmapheresis (DFPP) reduced the serum IgA paraprotein level with improvement of the sensory component of the polyneuropathy and decrease of soluble interleukin-6 receptor in the CSF. The remaining clinical features waned off after steroid treatment. The possible role of interleukin-6 in the pathogenesis of the Crow-Fukase syndrome and the utility of DFPP treatment are discussed.

Cooperative association of T cell beta receptor and HLA-DQ alleles in the production of anti-Ro in systemic lupus erythematosus.

The immunogenetics of the autoantibody response to Ro (or SS-A) have been explored in patients with systemic lupus erythematous. Data show that alleles of the T cell beta receptor and HLA-DQ loci are cooperatively associated with the presence of anti-Ro autoantibodies in systemic lupus erythematosus. Identification of HLA-DQ by oligonucleotide probe binding to polymerase chain reaction products demonstrates that the combination of DQB1*0201 and one of DQA1*0101, DQA1*0102, or DQA1*0103 is associated with anti-Ro. Patients possessing a particular pair of T cell receptor beta restriction enzyme polymorphisms along with these specific HLA-DQ alleles produce quantitatively more anti-Ro as measured by a sensitive solid-phase immunoassay than patients without these T cell receptor and DQ alleles. Other work has shown that the autoimmune response is directed against the human Ro antigen. These results are consistent with a central role in the disregulation of autoimmunity involving a trimolecular complex composed of the autoantigen bound by a HLA-DQ molecule which, together, are bound in turn by T cells which express a particular subset of T cell receptors.

3 cases of anti-Scl-70 (topoisomerase I) antibody associated with central nervous system lupus without renal disorder.

We describe 3 cases of systemic lupus erythematosus (SLE) associated with anti-Scl-70 antibody. Common symptoms were central nervous system disorder, discoid rash, lymphadenopathy, and no renal disorder. Two of 3 cases showed some symptoms of scleroderma but could not be diagnosed as such. Although further followup is required to determine if scleroderma develops, these unique symptoms might be a subtype of SLE or a lupus-like syndrome characterized by symptoms and anti-Scl-70 antibody.

Parkinson-like symptoms as a manifestation of systemic lupus erythematosus.

A 42-year-old Japanese woman with systemic lupus erythematosus (SLE) developed Parkinsonian-like movements. Steroid pulse therapy was most effective and additional anti-Parkinsonian drugs were not required. Although psychosis, seizures and meningitis are common central nervous system (CNS) manifestations in SLE patients, Parkinsonian-like symptoms are extremely rare. The putative genesis and treatment of CNS lupus are discussed.

The mapping of the human 52-kD Ro/SSA autoantigen gene to human chromosome 11, and its polymorphisms.

Autoantibodies to Ro/SSA occur in nearly half of the patients with systemic lupus erythematosus and are associated with lymphopenia, photosensitive dermatitis, and pulmonary and renal disease, which suggests that they have an immunopathologic role. The majority of Ro/SSA precipitin-positive patients produce serum antibodies that bind to the 60-kD and 52-kD Ro/SSA proteins. We previously isolated and determined the nucleotide sequence of a cDNA clone that encodes the 52-kD form of the human Ro/SSA protein. In the present study, we have determined the chromosomal location of the gene by in situ hybridization to the end of the short arm of chromosome 11. Hybridization of portions of the cDNA probe to restriction enzyme-digested DNA indicated the gene is composed of at least three exons. The exon encoding the putative zinc fingers of this protein was found to be distinct from that which encodes the leucine zipper. An RFLP of this gene was identified and is associated with the presence of lupus, primarily in black Americans.

[A case of systemic lupus erythematosus (SLE) developing pan-dysautonomia].

A 43-year-old woman who had been diagnosed as primary Sjögren's syndrome since 1986 developed severe constipation, urinary retention, dizziness at standing and polyarthralgia in February, 1990. Laboratory tests revealed proteinuria, hypocomplementemia and high titer of anti-DNA antibody. Diagnosis of SLE was made and she was admitted to our hospital on April 2, 1990. Physical examination on admission showed that she also had asymmetric pupils, impairment of sweating, orthostatic hypotension, neurogenic bladder, gastro-intestinal dysmotility and the diminution of R-R interval variability during deep breathing on the electrocardiogram. These findings suggested that she had pan-dysautonomia but there were no signs of motor and sensory disturbance. Because other diseases such as diabetes mellitus and amyloidosis which induced dysautonomia could be ruled out, her pan-dysautonomia seemed to be due to SLE. After the treatment with steroid pulse therapy, most of her dysautonomia improved rapidly. However, some of the disturbance had persisted for a long time. Pan-dysautonomia has been rarely reported as a complication of SLE, and high dose of steroid therapy at the early stage should be considered.