Anti-glucose-6-phosphate isomerase, anti-cyclic citrullinated peptide antibodies and HLA-DRB1 genotypes in Japanese patients with early rheumatoid arthritis.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: The majority of anti-GPI Ab-positive RA patients constitute a subset of HLA-DRB1* SE-associated, anti-CCP Ab-positive RA patients.

Differential association of HLA-DRB1 alleles in Japanese patients with early rheumatoid arthritis in relationship to autoantibodies to cyclic citrullinated peptide.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Time lag between active joint inflammation and radiological progression in patients with early rheumatoid arthritis.

OBJECTIVE: To determine clinical variables useful in predicting the prognosis of patients with early rheumatoid arthritis (RA) by investigating the relationship between clinical variables and radiological progression. METHODS: One hundred eighteen patients with early RA whose symptoms developed within the previous year were enrolled in a prospective study. Data from the 98 patients who completed the 2 year study were analyzed, using the number of erosive joints and Larsen's score as the outcome of RA. RESULTS: Increases in the number of erosive joints at 12 months after entry into the study were significantly correlated with the number of swollen joints (r = 0.510), erythrocyte sedimentation rate (ESR) (r = 0.404), and C-reactive protein (CRP) (r = 0.487) at 6 months. The same results were seen using Larsen's score as the measure of outcome. The average number of erosive joints or mean Larsen's score at 12 months was higher in patients whose levels of CRP were high at 6 months and suppressed by 12 months, but increased much less in patients whose levels of CRP were successfully suppressed by 6 months. More joint erosions were noted in patients with positive rheumatoid factor (RF) than in RF negative patients. CONCLUSION: Joint erosions appeared with a certain time lag after active synovitis. Earlier introduction of effective treatment is recommended for the prevention of RA joint damage. The presence of RF, number of swollen joints, ESR, and levels of CRP at 6 months after starting therapy are the most useful variables to predict radiological progression in patients with early RA.

Lack of association of HLA-DRB1 genotype with radiologic progression in Japanese patients with early rheumatoid arthritis.

OBJECTIVE: To evaluate the role of HLA-DRB1 genotypes in the development and progression of the rheumatoid arthritis (RA) disease process. METHODS: Patients with polyarthritis of < 1 year in duration were consecutively enrolled in the study. Other inclusion criteria were no diagnosis of inflammatory diseases other than RA, and no history of taking disease-modifying antirheumatic drugs or steroids. Patients were evaluated every 4 weeks, and radiographs of the hands/wrists and feet were taken at presentation and 1 year later. HLA-DRB1 genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: We enrolled 198 patients (median disease duration 5.0 months) and 150 controls. The frequency of individuals with DRB1*0405 and *0410 was significantly higher in the patients than in the controls. Homozygous states for DRB1 alleles with the RA-related shared epitope (SE) were associated with increased susceptibility for the development of polyarthritis (odds ratio 3.4, 95% confidence interval 1.5-7.7). None of the DRB1 alleles or SE genotypes correlated with the presence of bone erosion at presentation or 1 year later. CONCLUSION: DRB1 alleles with SEs were associated with the development of polyarthritis but not with early radiographic progression of the disease process.

Association of HLA class I and class II alleles with myositis in Japanese patients.

OBJECTIVE: To investigate the correlation of HLA class I and class II antigens and alleles with various forms of myositis in Japanese patients. METHODS: Eighty-four Japanese patients with myositis [22 with polymyositis (PM), 46 with dermatomyositis (DM), 16 with myositis overlapping with other collagen vascular diseases] were typed serologically for HLA-A, B, C antigens. HLA-DRB1, DQA1, and DQB1 alleles were determined by polymerase chain reaction dependent DNA typing methods. Fifty-eight Japanese controls were typed serologically while HLA-DRB1, DQA1, and DQB1 allele typing was carried out in 175, 95, and 104 controls, respectively. RESULTS: HLA-B7 was higher in patients than controls [20.2 vs 6.9% in controls: p=0.02, odds ratio (OR)=3.4]. The increase of HLA-B7 was largely dependent on the increase in overlap patients (37.5%; p=0.005, OR=8.1). HLA-A24 and B52 were significantly decreased in PM as compared to DM, while CW3 was significantly increased in PM versus DM. DRB1*08 alleles were significantly increased in patients (36.9 vs 20.5% in controls; p=0.004, OR=2.3), especially in PM and DM. DQA1*0501 and DQB1*0301 were significantly decreased in patients [4.8 vs 13.7% in controls; p=0.04, OR=0.32, and 8.3 vs 20.2% in controls; p=0.02, OR=0.36, respectively]. CONCLUSION: HLA-class I and class II alleles associated with Japanese patients with myositis may be different from those associated with Caucasian patients.

Guillain-Barré syndrome accompanied by central nervous system lupus in a patient with juvenile rheumatoid arthritis.

Abstract We describe a 17-year-old female with juvenile rheumatoid arthritis accompanied by Guillain-Barré syndrome (GBS) during the course of central nervous system (CNS) lupus. She initially developed CNS lupus, including headache and convulsion. A high-signal area in a magnetic resonance scan of her brain with T2-weighted images was noted, and her cerebrospinal fluid exhibited increased levels of IgG and interleukin-6. Eighteen days after the onset of CNS lupus, polyneuropathy in the lower extremities developed, and a diagnosis of GBS was made. No obvious preceding infections in the upper respiratory or gastrointestinal systems were noted before the onset of GBS, indicating that GBS might be part of the symptoms of CNS lupus.

[A case of microscopic polyangiitis with severe cardiac and respiratory muscle involvement].

A 66-year-old female was admitted to our hospital in January, 1998, complaining of low grade fever and muscle weakness of her legs. Physical examination revealed muscle weakness of her neck (4/5) and proximal skeletal muscles of her bilateral legs (3/5-4/5). She showed proteinuria and microhematuria. Her serum levels of ureanitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, creatinekinase, aldolase and myoglobin were all within the normal ranges. Antinuclear antibodies were negative, but her serum levels of pANCA (743 EU) and C reactive protein (18.0 mg/dl) were elevated. Neuroconduction velocity of her left common peroneal nerve was decreased to 40.8 m/sec and electric myograph showed neurogenic changes. Magnetic resonance images (MRI) of her bilateral thigh depicted high signal intensity in quadriceps by T 2 weighed images, but the signals were not enhanced by gadolinium injection. Muscle and renal biopsies revealed necrotizing vasculitis of the small arteries. Crescentic glomerulonephritis was also observed by renal biopsy. These findings supported the diagnosis of microscopic PN. On 16 th admission day, she developed acute cardiac and respiratory failures due to cardiac and respiratory muscle involvements with PN, and was assisted by mechanical ventilation. She was treated with methylprednisolone pulse therapy (500 mg/day, three consecutive days) on 18 th admission day, followed by 40 mg of oral prednisolone daily. However, her symptoms deteriorated, and herserum creatinine levels increased to 2.4 mg/dl. On 24 th admission day, intravenous cyclophosphamide pulse therapy (500 mg/day) was instituted. Her cardiac wall motion on echocardiography and serum creatinine levels gradually improved, but her skeletal and respiratory muscle weakness did not improve. On 38 th admission day, she was complicated with respiratory infection by methicillin resistant Staphylococcus aures. On 62 th admission day, she died of endotoxic shock. This is the first report describing respiratory muscle involvement with PN, and the second report describing MRI findings of muscle involvement by PN. Therefore, our case provides important clinical information for the diagnosis and treatment of the disease.

[A case of Sjögren's syndrome and systemic sclerosis complicated with acute pancreatitis].

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.