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Genetic variations in cardiac ion channels have been implicated not only as the causes of inherited arrhythmic syndromes, but also as genetic risk factors for some acquired arrhythmias. To elucidate the potential roles of genetic polymorphisms of the alpha subunit of the voltage-gated sodium channel type V (SCN5A) in cardiac rhythm disturbance, the entire SCN5A coding exons and their flanking introns were sequenced in 166 Japanese arrhythmic patients and 232 healthy controls. We detected 69 genetic variations, including 54 novel ones. Out of the 12 novel nonsynonymous single nucleotide polymorphisms (SNPs), p.Leu1988Arg was found at a frequency of 0.015. The other 11 SNPs were rare (0.001), with 6 found in arrhythmic patients and 5 in healthy controls. The frequency of a novel intronic SNP, c.703+130G>A, was significantly higher in the patients than in the controls, suggesting this SNP is associated with an unknown risk factor for arrhythmia. Following linkage disequilibrium analysis, the haplotype structure of SCN5A was inferred using high-frequency SNPs. The frequency of the haplotype harbouring both p.Leu1988Arg and the common SNP p.His558Arg (haplotype GG) was significantly lower in the patients than in the controls. This finding suggests that this haplotype (GG) might have been positively selected in the controls because of its protective effect against arrhythmias. This study provides fundamental information necessary to elucidate the effect of genetic variations in SCN5A on channel function and cardiac rhythm in Japanese, and probably in the Asian population.

The diurnal change of sUA and the effect of febuxostat on this change were investigated in 10 patients with gout and/or hyperuricemia. The diurnal sUA change after the last dose during the 4-week treatment phase (20 mg, QD) was almost the same as the pre-treatment value. Considering the dose, the AUC(obs) and Cmax of unchanged drug in patients with gout and/or hyperuricemia were estimated to be similar to those of healthy male adults. The results show that a 6-week treatment with febuxostat is safe and well-tolerated in the target patient population for this drug.

The outcome of treatment with disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients is considerably variable and is also unpredictable. It would be useful clinically if physicians were able to predict responses to DMARDs prior to their administration. One possible cause of differences in efficacy and adverse drug reactions is genetic variation in how individuals metabolize drugs. Based on pharmacogenetics, tailor-made drug therapy, also called personalized drug therapy or individual drug therapy, will be possible with analysis of genetic polymorphism, such as single nucleotide polymorphism (SNP), and analysis of haplotype and diplotype configuration. Several studies of the correlation between the genetic polymorphism of enzymes metabolizing several DMARDs and efficacy or adverse drug reactions have already been reported, suggesting that pharmacogenetics will be applicable to the treatment of RA in the near future.

SUMMARYVascular damage in systemic sclerosis (SSc) may be a factor in the abnormal regulation of several vasoactive agents. It has been well confirmed that plasma endothelin-1, as a vasoconstrictive factor, is elevated in patients with SSc. However, it is still controversial whether the levels of serum nitric oxide (NO), a strong vasodilator, are increased or decreased in SSc patients compared to healthy donors. In this study, we measured the levels of serum NO metabolites in SSc patients and determined the contribution of the excessive production of NO synthase (NOS)-2 by skin fibroblasts to NO synthesis. Serum NO levels of 45 patients with SSc were significantly higher than those of 20 healthy volunteers. In addition, some clinical features of SSc (the extent of skin fibrosis, short disease duration, and the complication of active fibrosing alveolitis) were all correlated positively with the levels of NO metabolites in SSc patients. To evaluate the levels of NOS-2 produced by skin fibroblasts, skin fibroblast cultures were established from SSc patients and healthy volunteers. Reverse transcription-polymerase chain reaction indicated that NOS-2 mRNA was spontaneously expressed in cultured fibroblasts derived from SSc patients, but not in those derived from healthy normal controls. Immunohistochemical staining also showed that NOS-2 proteins were detected in SSc fibroblasts but not in normal fibroblasts. The production of NO by cultured fibroblasts was visualized directly by a reagent (DAF-2 DA) used for the fluorescent detection of NO. Cultured SSc fibroblasts were capable of NO synthesis in culture media containing l-arginine, whereas normal fibroblasts (with no expression of NOS-2) did not synthesize detectable NO. These observations indicate that NO production is increased markedly in early-stage diffuse cutaneous SSc patients with active fibrosing alveolitis, and that constitutive NOS-2 expression in SSc fibroblasts may contribute to increased NO production.

To examine whether polymorphism at the SAA loci is associated with the development of amyloid protein A (AA)-amyloidosis, we determined the genotypes at the SAA1 and SAA2 loci in 43 AA-amyloidosis patients (amyloidosis population) and 77 patients with rheumatoid arthritis (RA) who had been ill for less than 5 years (early RA population). We also compared the frequencies of the genotypes at the SAA1 locus among 90 Korean, 95 Taiwanese, and 103 Japanese healthy subjects. The frequencies of the gamma/gamma genotype and gamma alleles at the SAA1 locus were significantly higher in the amyloidosis population than in the early RA population (34.9% versus 7.8%, and 58.1% versus 33.8%, chi2 test P=0.0001). The frequencies of the gamma allele at the SAA1 locus in Koreans, Taiwanese, and Japanese were 41.6%, 35.6%, and 37.4%, respectively. The length of the latent period of AA-amyloidosis was significantly longer in the patients with smaller numbers of the gamma allele at the SAA1 locus (Spearman's correlation coefficient: -0.42, P

Obesity and insulin resistance have been reported as negative predictors for sustained virological response (SVR) in hepatitis C virus (HCV) genotype 1 infected patients treated with pegylated interferon-α plus ribavirin. They are also known to affect serum levels of several cytokines including adipocytokines. But the association between these cytokines and treatment outcome has not been fully elucidated. We examined pretreatment serum levels of 14 cytokines among 190 patients who were treated with pegylated interferon-α-2b plus ribavirin for chronic HCV-1b infection with high viral load (≥ 5 log IU/mL) and analyzed their contribution to treatment response. Plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor, and 11 clinical factors showed significant association with SVR in univariate logistic regression analysis. Four significant factors in multivariate analysis; serum PAI-1 (odds ratio [OR] = 15.42), body mass index (OR = 4.56), rs8099917 (OR = 4.95) and fibrosis stage (OR = 5.18) were identified as independent predictors. We constructed a simple and minimally invasive prediction score for SVR based on the presence of these factors except for fibrosis stage. The accuracy of this score was 73%, and was confirmed using an independent validation cohort consisting of 31 patients (68%). The strongest correlation was between PAI-1 level and platelet count (r = 0.38, P = 1.8 × 10(-7)), and PAI-1 level was inversely correlated with fibrosis stage. Serum PAI-1 is a novel predictor for the response to combination therapy against chronic HCV-1b infection and may be associated with liver fibrosis.

Our goal was to evaluate the associations of antibodies (Abs) to glucose-6-phosphate isomerase (GPI) with Abs to cyclic citrullinated peptide (CCP) and HLA-DRB1 genotypes in Japanese patients with early rheumatoid arthritis (RA).One hundred and eight patients with early RA (85 female, 23 male) who visited our clinic within 1 year of symptom onset were examined for anti-GPI and anti-CCP Ab levels, and HLA-DRB1 genotype. Anti-GPI and anti-CCP Ab levels, and HLA-DRB1 genotypes were also determined in 63 controls and 265 healthy controls, respectively.Of the 108 patients with early RA and the 63 controls, 20 (18.5%) and 3 (4.8%) were anti-GPI Ab-positive, respectively. Of the 20 patients with anti-GPI Abs, 17 (85%) were positive for anti-CCP Abs. HLA-DRB1*0405 and shared epitope (SE) carrier frequencies were significantly increased not only in anti-GPI Ab-positive patients (p=0.00057, odds ratio [OR] 4.6, 95% CI 1.8-11.8; p=0.0011, OR 5.0, 95% CI 1.7-14.0), but also in anti-GPI Ab-negative patients (p=0.0017, OR 2.2, 95% CI 1.3-3.7; p=0.00011, OR 2.6, 95% CI 1.6-4.3), when compared with controls. In addition, the carrier frequency of HLA-DRB1*1201 was significantly increased in anti-GPI Ab-positive patients compared with controls (p=0.0056, OR 4.3, 95% CI 1.4-13.2).The majority of anti-GPI Ab-positive RA patients constitute a subset of HLA-DRB1* SE-associated, anti-CCP Ab-positive RA patients.

Objectives. To investigate the association between single-nucleotide polymorphisms (SNPs) in the pulmonary surfactant protein (SP) genes and the presence or absence of interstitial lung disease (ILD) in SSc patients. Methods. We studied 127 Japanese patients with SSc and 206 normal subjects. Investigated SNPs were C/T within amino acid (aa) 219, Arg219Trp in the SP-A1 gene (rs4253527), C/T within aa 131 (at nucleotide 1580) and Thr131Ile of the SP-B gene (rs1130866). Genotypes were determined by the TaqMan method. Results. Genotype frequencies were not different between the SSc patients and normal controls for both loci. The patients were subsequently divided into two groups based on presence or absence of ILD. In the SNP in the SP-B gene, the frequency of the T/T genotype was significantly lower in the patients with ILD than in those without ILD. Limited in the patients who were positive for anti-Scl-70 antibody, the difference in the frequency of the T/T genotype between the ILD-positive and ILD-negative groups became more apparent. On the other hand, in the SNP in the SP-A1 gene, there was no significant skewing for a certain genotype. Conclusion. In SSc, where massive fibrosis occurs, possession of the T/T genotype in the SP-B gene would reduce the risk of ILD in Japanese.

2,8-Dihydroxyadenine (DHA) lithiasis is a rare type of urinary stone disease and the deficiency of adenine phosphoribosyltransferase (APRT) activity is known to be the cause of this disease. To identify a 2,8-DHA stone is important because this stone is well managed by medical therapy. Regarding a radiological finding, previous reports have considered 2,8-DHA to be radiolucent like uric acid stone. This report is a case of radiopaque 2,8-DHA stone and proposes that the composition of urinary stones should always be investigated for adequate medical treatment.

We describe two cases of Behçet's disease in a 37-year-old woman and a 40-year-old woman. Each of these patients developed cryptogenic organizing pneumonia associated with Behçet's disease. Both patients developed fever, cough and pleuritic chest pain during follow-up by our out-patient clinic. Chest X-rays and computed tomographies developed ground glass opacity, peripheral nodular opacities and consolidations. There were neither thrombosis nor aneurysm findings. Both cases were diagnosed as having organizing pneumonia. Prednisolone (40-60 mg/day) showed clinical and radiological improvement for both cases. Lung involvement is a rare feature of Behçet's disease, sometimes leading to a poor prognosis. The pulmonary parenchymal involvement still needs to be explored fully to diagnose early and start proper treatment. These two rare cases provide clinical insight into lung involvement in Behçet's disease.

To evaluate the role of HLA-DRB1 genotypes and antibodies to cyclic citrullinated peptides (anti-CCP antibodies) in the development and radiographic progression of Japanese patients with rheumatoid arthritis (RA).One hundred and ten patients with early RA (88 female, 22 male) who visited our clinic within 1 year of symptom onset were examined for anti-CCP antibody levels and HLA-DRB1 genotypes. HLA-DRB1 genotypes were also determined in 265 healthy controls. Radiographic progression over a 2-year interval was evaluated using the Larsen's method in 66 patients.Among the 110 patients with early RA, 82 patients (74.5%) were anti-CCP positive. Carrier frequency of HLA-DRB1*0405 was significantly increased in RA patients with anti-CCP antibodies compared with controls and RA patients without anti-CCP antibodies (odds ratio [OR] 3.4, 95% confidence interval [95% CI] 2.0-5.7 and OR 3.3, 95% CI 1.3-8.6, respectively). Carriership of one or two SE alleles was significantly associated with production of anti-CCP antibodies (OR 2.7, 95% CI 1.1-6.7 and OR 9.3, 95% CI 1.1-78.2, respectively). On the other hand, allele frequency of HLA-DRB1*0901 was significantly increased in RA patients without anti-CCP antibodies compared with controls and RA patients with anti-CCP antibodies (OR 2.2, 95% CI 1.1-4.1 and OR 3.0, 95% CI 1.4-6.4, respectively).In Japanese patients with RA, HLA-DRB1 SE alleles are associated with production of anti-CCP antibodies and HLA-DRB1 alleles appear to be differently associated with early RA depending on anti-CCP positivity as in Caucasian patients with RA.

We describe two cases, a 28-year-old woman and a 46-year-old man, with mouth and genital ulcers with inflamed cartilage (chondritis of the nose and ears) (MAGIC syndrome). The conditions of both patients were resolved by treatment with corticosteroid and colchicine. We also review the English literature related to this rare syndrome.

As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks -1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms -1,789GA in the distal promoter region and IVS5 + 123AG in intron 5 was identified. We re-assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally-important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease-association studies carried out using Asian subjects.

Vitamin K is used for protecting against osteoporosis. Recently, it has been reported that the inhibitory effect of vitamin K(2) (menatetrenone) on bone resorption may be related to its side chain. Geranylgeranylacetone (GGA), known as teprenone, an antiulcer drug, has almost the same chemical structure as that of the side chain of menatetrenone. We hypothesized that GGA also has an inhibitory effect on osteoclastogenesis both in vitro and in vivo. GGA in pharmacological concentrations directly inhibited osteoclastogenesis from human monocytes induced by soluble receptor activator of nuclear factor-kappaB ligand. In addition, GGA induced degradation of actin rings in mature osteoclasts, which was reversed by adding geranylgeranylpyrophosphatase. Moreover, GGA increased the bone mineral density of total femur, proximal metaphysis, and diaphysis of femur in ovariectomized rats. GGA also prevented bone loss induced by hindlimb unloading in tail-suspended rats. These results indicate that GGA prevents bone loss by maintaining a positive balance of bone turnover through suppression of both the formation and the activity of osteoclasts. Thus, GGA could be used to prevent and improve osteoporosis.

Genetic variations in cardiac ion channels have been implicated not only as the causes of inherited arrhythmic syndromes, but also as genetic risk factors for some acquired arrhythmias. To elucidate the potential roles of genetic polymorphisms of the alpha subunit of the voltage-gated sodium channel type V (SCN5A) in cardiac rhythm disturbance, the entire SCN5A coding exons and their flanking introns were sequenced in 166 Japanese arrhythmic patients and 232 healthy controls. We detected 69 genetic variations, including 54 novel ones. Out of the 12 novel nonsynonymous single nucleotide polymorphisms (SNPs), p.Leu1988Arg was found at a frequency of 0.015. The other 11 SNPs were rare (0.001), with 6 found in arrhythmic patients and 5 in healthy controls. The frequency of a novel intronic SNP, c.703+130GA, was significantly higher in the patients than in the controls, suggesting this SNP is associated with an unknown risk factor for arrhythmia. Following linkage disequilibrium analysis, the haplotype structure of SCN5A was inferred using high-frequency SNPs. The frequency of the haplotype harbouring both p.Leu1988Arg and the common SNP p.His558Arg (haplotype GG) was significantly lower in the patients than in the controls. This finding suggests that this haplotype (GG) might have been positively selected in the controls because of its protective effect against arrhythmias. This study provides fundamental information necessary to elucidate the effect of genetic variations in SCN5A on channel function and cardiac rhythm in Japanese, and probably in the Asian population.

Inflammatory mediators such as interleukin-6 and tumor necrosis factor-alpha play an important role in the pathogenesis of rheumatoid arthritis (RA) by promoting chronic inflammation and joint damage. NF-kappaB is a transcriptional activator of genes for these cytokines. It also plays an important role in the regulation of osteoclast differentiation which plays a key role in joint destruction in RA. Ligands for peroxisome proliferator-activated receptor (PPAR) -gamma have recently been reported to inhibit the development of RA. In this study, we investigated the role of PPARalpha in RA.We analyzed the protein expression of PPAR-alpha and -gamma in rheumatoid synovial fibroblasts (RSF) from RA patients and analyzed the effects of ligands for PPAR-alpha and -gamma on cytokine production from RSF NF-kappaB activations in RSF and osteoclast differentiation from osteocalst progenitor in the peripheral blood. Moreover, we analyzed the effects of oral administration of PPAR-alpha and -gamma ligands on the development of adjuvant-induced arthritis (AIA) in female Lewis rats.We confirmed the expression of PPAR-alpha in RSF and also demonstrated that fenofibrate, a ligand for PPAR-alpha, inhibited cytokine production from RSF, NF- kappaB activation in RSF, and osteoclast differentiation from osteoclast progenitor cells. Furthermore, we demonstrated that fenofibrate inhibits the development of arthritis in a rat model of human RA.These results indicate that fenofibrate suppresses the development of arthritis by inhibition of NF-kappaB signaling; therefore, this compound offers possible anti-rheumatic drug.

APOE polymorphisms were studied in 200 unrelated patients with primary dystonia as well as 300 age-matched control subjects. Although no difference was found in APOE genotype between the patients with dystonia and the controls, APOE-epsilon4 carriers developed the disease on average approximately 10 years earlier than APOE-epsilon4 noncarriers (p = 0.0012). This suggests that APOE-epsilon4 genotype affects the clinical presentation of primary dystonia.

Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P=0.00059, Fischer's exact probability test, odds ratio [OR]=7.81, 95% confidence interval [95% CI]=2.48–24.65) and the RA patients (P=0.015, Fischer's exact probability test, OR=4.0, 95% CI=1.39–11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.

Specimens of synovial tissues from 5 affected joints of 3 patients with Behçet's disease were available for histopathological examination. All specimens were infiltrated by lymphocytes and neutrophils, and exhibited marked vascularity and infiltration of lymphoid cells among the vessels. Marked plasma cell infiltration and lymphoid follicle formation were found in one synovial tissue sample. There was no evidence of infection or vasculitis. These findings suggest that the histopathological characteristics of synovial tissue in Behçet's disease may have a wide range, some of which may even resemble the synovial tissue of rheumatoid arthritis.

Haplotype analysis is important for mapping traits. Recently, methods for estimating haplotype frequencies from genotypes of unrelated individuals based on the expectation-maximization (EM) algorithm have been developed. Our program estimates haplotype frequencies in the population and determines the posterior probability distribution of diplotype configuration (diplotype distribution) for each subject based on the estimated haplotype frequencies. Samples from three ethnic groups for the smoothelin gene (SMTN) and those from three Japanese groups for serum amyloid A genes (SAA@) were analyzed. The estimated diplotype distribution for each individual was concentrated, in most cases, in a single diplotype configuration. The diplotype configuration thus determined was the same as that determined in in vitro experiments, with one exception. Thus, the diplotype configurations determined using the estimated haplotype frequencies from unrelated individuals are reliable. Using this method, the risk of a subject developing a phenotype may be estimated from the diplotype distribution when the phenotype is associated with diplotype configurations.

Expression and function of tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in synovia of patients with rheumatoid arthritis (RA) were examined to investigate posttranslational regulation of TNF-alpha production by TACE in RA.Expression of TACE protein was evaluated by immunohistochemistry. Cytokines and soluble cytokine receptors were measured by ELISA. TACE mRNA was detected by RT-PCR. The enzymatic activity of TACE was measured using TACE-specific fluorogenic substrate.Expression of TACE at protein level in synovial tissue (ST) of patients with RA was significantly stronger than that of patients with osteoarthritis (OA). In RA, TACE was mainly expressed in CD68+ macrophage-like synovial cells. ST from 9 of 9 RA and 3 of 8 OA patients expressed TACE mRNA. RA ST cells possessed significantly higher TACE-like enzymatic activity than OA ST. A synthetic TACE inhibitor significantly reduced the release of TNF-alpha and p75 TNF receptor from RA ST cells.TACE is an important regulator of the secretion of TNF-alpha from synovia of patients with RA.

To investigate the expression and function of interleukin 18 (IL-18) in synovial tissue (ST) of patients with rheumatoid arthritis (RA).The localization of IL-18 in ST was analyzed by immunohistochemistry. IL-18 and IL-18 receptor (IL-18R) mRNA were detected by RT-PCR. Expression of IL-18 at the protein level was analyzed by Western blotting. Cytokines in culture supernatants were measured by ELISA.From immunohistochemical analysis, IL-18-producing cells were localized in the lining layer and sublining region of RA ST. Most of them coexpressed CD68 antigen. In ST from patients with osteoarthritis (OA), IL-18-producing cells were localized only in the sublining region and the numbers of these cells were small. From RT-PCR, RA ST expressed mRNA of IL-18, as well as alpha- and beta-chains of IL-18R. OA ST did not express or very weakly expressed mRNA of alpha- and beta-chains of IL-18R. ST from RA patients produced significantly larger amounts of IL-18 in vitro than OA ST. Western blotting revealed that RA ST expressed mature IL-18 more abundantly than OA ST. IL-12 alone stimulates interferon-gamma (IFN-gamma) production by RA synovial tissue cells, but IL-18 alone could not. In the presence of IL-12, however, IL-18 could synergistically stimulate IFN-gamma production by RA synovial tissue cells. OA synovial tissue cells responded to neither IL-12 nor IL-12 + IL-18. IL-18 showed synergistic effects with IL-12 on promoting the ability of synovial T cells from RA patients to produce IFN-gamma.These findings suggest that mature IL-18 is expressed in RA synovia and contributes to the production of IFN-gamma by infiltrating T cells.

Hemophagocytic syndrome (HPS) is characterized by the activation of the mononuclear phagocytic system with prominent hemophagocytosis in the bone marrow and reticuloendothelial systems, and its occurrence is usually associated with variable disorders such as viral infections and malignant lymphoma. Recently, it was reported that HPS also occurred in association with underlying connective tissue disease, especially systemic lupus erythematosus. We report here a case of recurrent HPS complicated with systemic sclerosis. A 32-year-old woman had been diagnosed as systemic sclerosis since 1994. She was admitted due to unknown high fever and severe pancytopenia in 1997, and the diagnosis of HPS was determined because of hemophagocytosis in bone marrow and hyperferritinemia. Her symptoms were improved by immunosuppressive therapies including steroid pulse therapy and oral prednisolone (60 mg/day). She was followed by the treatment of oral prednisolone which was gradually tapered in our out-patient clinic. In August of 1999 high fever and severe anemia were recurred, and she was admitted again to our hospital because of the diagnosis as recurrent HPS. She had been treated with 40 mg/day of oral prednisolone and fever was immediately disappeared and hemoglobin was gradually increased. HPS is considered to be a rare complication with systemic sclerosis, and the etiology has been unknown. IL-18 is a novel cytokine which is a potent inducer of interferon-gamma, and its properties may be a proinflammatory regulation and activation of monocyte/macrophage and histiocyte through the expression of interferon-gamma. Therefore, the significance of IL-18 in the pathophysiology of HPS was recently reported. In this case, we investigated the significance of IL-18 and revealed the levels of serum IL-18 were well correlated with disease activity of HPS.

To address whether the gamma haplotype at exon 3 of the SAA1 gene is directly associated with type AA amyloidosis or is merely in linkage with an unknown polymorphism that is primarily associated with disease risk, we examined the SAA1 gene for new polymorphisms.We analyzed DNA samples from 44 rheumatoid arthritis (RA) patients with AA amyloidosis (amyloid group), 55 RA patients without AA amyloidosis (RA group), and 58 non-RA healthy subjects (non-RA group). We also examined DNA samples from 50 Caucasians to compare linkage disequilibrium relationships involving SAA1 region polymorphisms between Japanese and Caucasoid populations.We observed 3 novel single-nucleotide polymorphisms (SNPs) in the 5'-flanking region of SAA1: -61C/G, -13T/C, and -2G/A. Comparison of allele frequencies and ratios of individuals with particular alleles between the study groups revealed statistically significant differences between the amyloid and RA groups and between the amyloid and non-RA groups. Statistical analysis revealed that the -13T/C SNP was strongly associated with AA amyloidosis. In addition, we found tight linkage between the -13T allele and the alpha haplotype, rather than the beta haplotype, at exon 3 in the Caucasoid population, while -13T was closely linked to the gamma and beta haplotypes, rather than the alpha haplotype, in the Japanese population. Since the linkage disequilibrium relationship was reversed between the Japanese and Caucasoid populations, different exon 3 haplotypes of SAA1 are found to be associated with the risk of AA amyloidosis in different ethnic groups.Our data suggest that the SAA1 -13T allele, rather than SAA1 exon 3 haplotypes, is primarily associated with AA amyloidosis risk.

To investigate the differences between orthopedists and internists in indications for surgical management in patients with rheumatoid arthritis (RA), a questionnaire-based survey was performed on the Internet with the presentation of a case of progressive RA along with serial X-ray films of the knee. Ninety-three doctors (43 orthopedists and 50 internists, average age: 49.2 years) answered the questionnaire. Most of the doctors who viewed the X-ray film showing Larsen's grade IV chose that as the optimal time for total knee arthroplasty. No difference was noted in their choice between orthopedists and internists. Opinions varied widely, however, among younger doctors, but there was agreement among older doctors, suggesting the effect of the study and experience. On the other hand, some doctors recommended arthroscopic synovectomy for knees in the earlier stages of RA, but others did not recommend the arthroscopic surgery itself. Although this new methodology might include possible biases, we believe it should be considered in the research of rheumatology.

A 56-year-old woman with rheumatoid arthritis (RA) suddenly developed severe respiratory distress and laryngeal stridor, which required endotracheal intubation. She had had RA for 12 years, which had been controlled well with prednisolone (3 mg/day) at the orthopedic clinic. Laryngoscopy revealed cricoarytenoid arthritis. She was finally diagnosed as having overlap syndrome with RA and systemic lupus erythematosus. She was given high dose corticosteroids that improved her clinical symptoms and laryngoscopic findings. She represents the first patient with overlap syndrome who developed an acute airway obstruction due to cricoarytenoid arthritis.

A 39-year-old man, who had been treated with Etretinate for common wart since he was 29 years old, was admitted to Taga General Hospital complaining of gradually deteriorating lumbago and bilateral hip joints pain in September, 1996. His lower vertebrae and bilateral hip joints showed abnormal ossification on X-ray. The bone scintigraphy indicated the existence of sacroiliitis. His platelet counts were fluctuating between 8 x 10(4) and 9 x 10(4)/mm3. During the follow-up in our out-patient clinic, he was suddenly suffered from severe abdominal pain in August, 1997 and admitted to our hospital. An emergency operation revealed multiple ulcers of his ileum with several perforations. Histological findings of the specimen of the ileum showed simple ulcer. After the operation, he had oral and genital ulcers. He did not have any signs or symptoms of ocular involvement. He was diagnosed as intestinal Behçet's disease. Because he showed gradually pancytopenia for several months after the operation, bone marrow aspiration was performed and a diagnosis of refractory anemia, a type of myelodysplastic syndrome (MDS), with trisomy of chromosome 8 was made. Abnormal ossification of his vertebrae and hip joints were considered to be related to Behçet's disease because an coexistence with sacroiliitis. On the other hand, there is no denying the effects of orally Etretinate administration. Several cases have been reported the association of MDS with Behçet's disease. In this case, the existence of MDS or various symptoms in Behçet's disease became apparent after the perforation of ileum ulcer. This paper discusses possible etiology of the relation between Behçet's disease and MDS, or the characteristic clinical course in this case.

We report here a case of interstitional pneumonia (IP) associated with amyopathic dermatomyositis (DM). In August, 1998, a 53-year-old Japanese man was admitted to our hospital because of fever, polyarthritis and erythematous heliotrope eruption and Gottron's sign without any symptom of myositis. Serum CK level and EMG were normal. Jo-1 antibody was negative. Chest computed tomography (CT) revealed IP at both lung base areas. The patient was diagnosed as amyopathic DM with IP. When IP rapidly progressed, methylprednisolone pulse therapy and oral high dose prednisolone were not effective. High-dose intravenous cyclophosphamide seemed to be transiently effective, but oral cyclosporine A was not effective. The patient was died of respiratory failure in October 1998. During the course, we measured serum levels of LDH, sIL-2 R, s-ICAM-1 and KL-6, KL-6 could be a sensitive parameter of IP activity.

A 25-year-old Japanese woman with systemic lupus erythematosus (SLE) had myocardial dysfunction. Heart catheterization showed normal coronary anatomy. Left ventricular cineangio-graphy demonstrated hypokinesis in the anterior and posterior segments. Myocardial scintigraphy revealed patchy defects in the regions unrelated to coronary arteries. These data suggested that the myocardial dysfunction was due to microvasculopthy. In addition, it was speculated that the microvasculopathy was caused by vasculitis but not by thrombi, since she did not have antiphospholipid syndrome. In support of this speculation, corticosteroid therapy without any thrombolytic agents was effective. This report represents the first live patient with SLE in whom myocardial dysfunction due to microvasculopathy has been demonstrated.

We report a case of Sjögren's syndrome (SS) and systemic sclerosis (SSc) complicated with acute pancreatitis. A 51-year-old woman had been diagnosed as SS in 1973. She noticed Raynaud's phenomenon in 1977. In 1988, interstitial pneumonia (IP) was pointed out and she was treated with methylprednisolone (mPSL) pulse therapy. Prednisolone (PSL) was gradually tapered to 3-5 mg daily and she visited our outpatient clinic in 1995. On her first admission to our hospital in 1996, she showed xerostomia, keratoconjunctivitis sicca, sclerotic skin changes of her distal extremities and face, thickening of her sublinguinal frenulum, and regurgitative esophagitis. She was positive with anti-SS-A and SS-B antibodies. She was diagnosed as SS and SSc. Radiographic and laboratory data also established the diagnosis of inactive IP, renal tubular acidosis (RTA) and chronic renal failure (CRF). In April 30th 1997, she was admitted to our hospital again with complaints of dyspnea, dysesthesia, epigastralgia and petechia. Active IP and mononeuritis multiplex were diagnosed, and petechia was considered to be associated with vasculopathy. Her serum amylase level was 891 mU/ml on admission and spontaneously increased to 2440 mU/ml on May 12th along with increase of fibrinogen degradation product, D-dimer and alpha 2 plasmin-plasmin inhibitor complex levels. Ultrasonography depicted swelling of her pancreatic head and the diagnosis of acute pancreatitis was made. She was treated with protease inhibitors and intravenous hyperalimentation for acute pancreatitis. mPSL pulse therapy (500 mg/day for 3 days) was instituted for IP and mononeuritis multiplex on May 22, followed by 50 mg of daily PSL. While IP and mononeuritis multiplex gradually improved by the high-dose steroid therapy, serum amylase level raised to more than 4293 mU/ml, suggesting the modification of pancreatitis by the treatment with steroid. Since she did not respond to the conservative therapy for acute pancreatitis, she was treated with plasmapheresis, which turned out to be very effective. However, she was suffered from fungal pneumonia and died of respiratory failure. As far as we know, only three cases of SS with acute pancreatitis have been reported so far. The immunopathological mechanisms of development of acute pancreatitis in our case, especially focusing on the significance of microvasculopathy and hypercoagulability, were discussed.