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.

Cryptogenic organizing pneumonia in two patients with Behçet's disease.

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.

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.

Two Japanese cases with MAGIC syndrome (mouth and genital ulcers with inflamed cartilage).

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.

Synovial histology in three Behçet's disease patients with orthopedic surgery.

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.

Rapidly progressive glomerulonephritis with D-penicillamine.

We present 3 cases of anti-myeloperoxidase, anti-neutrophil cytoplasmic antibody (MPO-ANCA)-positive rapidly progressive glomerulonephritis developed during the treatment with D-penicillamine (D-PC) for rheumatoid arthritis. Rheumatoid arthritis was diagnosed in these patients, and D-PC was administered to them at doses of 100, 200, and 300 mg per day for 32, 42, and 39 months, respectively. They developed proteinuria, hematuria, renal insufficiency, and anemia, and D-PC was stopped. On admission, MPO-ANCA was strongly positive in their sera. Renal biopsy showed glomerulonephritis with cellular crescents. Immunofluorescence examination revealed deposits of granular IgG, IgM, IgA, C1q, and C3 in the mesangium. The 3 patients were treated with steroid pulse therapy along with administration of anticoagulants, and cyclophosphamide was also used in 2 patients. Their renal function improved gradually and MPO-ANCA disappeared after immunosuppressive treatment.

Progressive appearance of overlap syndrome together with autoantibodies in a patient with fatal thrombotic microangiopathy.

We describe an extraordinary patient with overlap syndrome (systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis) having positive autoantibodies against Sm, double stranded DNA, DNA topoisomerase I, and centromere, together with rheumatoid factor. The patient had multiple organ involvement resulting from thrombotic microangiopathy that mimicked so-called normotensive scleroderma renal crisis, and died mainly of massive pulmonary hemorrhage caused by thrombotic thrombocytopenic purpura. The clinical presentations of the case support the concept of strong associations between disease-specific autoantibodies and clinical features.

Pancytopenia and colitis with Clostridium difficile in a rheumatoid arthritis patient taking methotrexate, antibiotics and non-steroidal anti-inflammatory drugs.

Methotrexate (MTX) is widely used despite its side-effects. We describe a rheumatoid arthritis (RA) patient taking low-dose MTX who developed severe pancytopenia and colitis with Clostridium difficile after the administration of antibiotics for acute pyelonephritis. Our case suggests that low-dose MTX may seriously interact with antibiotics and that these side-effects should always be considered when RA patients are treated with MTX and antibiotics.

[MPO-ANCA positive rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with D-penicillamine].

We present here a case of MPO-ANCA positive rapidly progressive glomerulonephritis (RPGN) after 34 months of D-penicillamine (D-PC) therapy for rheumatoid arthritis (RA). A 27-year-old Japanese woman was diagnosed as having RA in June 1994 at our out-patient clinic. Oral D-PC administration was initiated at a dose of 100 mg per day in January 1995. In August 1997, proteinuria, hematuria, renal insufficiency, and anemia developed. D-PC was withdrawn promptly, and prednisolone 5 mg per day was started. The patient was admitted to our hospital in September. On admission, anti-neutrophil cytoplasmic antibody against mycloperoxidase (MPO-ANCA) was strongly positive in the serum. Renal biopsy showed glomerulonephritis with cellular crescent formation in 60% of the glomeruli observed. Immunofluorescence examinations revealed deposits of granular IgG, IgA, C 1 q, and C 3 in the mesangium. The patient was treated with steroid pulse therapy along with administration of anti-coagulation and anti-platelet agents under the diagnosis of MPO-ANCA positive D-PC-induced RPGN. The renal function was gradually recovered and MPO-ANCA disappeared. Since RPGN is potentially a fatal disease, frequent monitoring of renal function and discontinuation of D-PC are required. In case MPO-ANCA becomes positive, prompt and correct diagnosis of the renal disorder could lead to a good prognosis as in this case. The present case may provide some important immunological insights into medical procedures to treat D-PC-induced RPGN and MPO-ANCA related glomerulonephritis.

Geranylgeranylacetone inhibits formation and function of human osteoclasts and prevents bone loss in tail-suspended rats and ovariectomized rats.

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.

Systemic lupus erythematosus with myocardial dysfunction due to microvasculopathy.

A 25-year-old Japanese woman with systemic lupus erythematosus (SLE) had myocardial dysfunction. Heart catheterization showed normal coronary anatomy. Left ventricular cineangiography 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.

[A case of amyopathic dermatomyositis with rapidly progressive interstitial pneumonia].

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.

Cricoarytenoid arthritis with rheumatoid arthritis and systemic lupus erythematosus.

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.

[Alkaline phosphatase (ALP) activity in rheumatoid arthritis (RA): its clinical significance and synthesis of ALP in RA synovium].

Increased concentration of serum alkaline phosphatase (ALP) is a common feature in rheumatoid arthritis (RA), although its origin remains unclear. The aim of this study is to analyze the origin and clinical significance of the elevated ALP value in RA. In 123 RA and 63 age- and sex-matched OA (osteoarthropathy) patients, concentrations of total ALP and its isozymes in serum and synovial fluid were studied. Serum CRP, Fe, ferritin, and Cu values were examined, respectively. The expression of ALP as protein was also investigated by using an enzymehistochemical and an immunohistochemical staining methods. Serum ALP values were elevated in 37.4% of RA (245.2 +/- 91.2 IU/L), and significantly higher than those of OA (192.3 +/- 45.2 IU/L: P < 0.01, RA v.s. OA). The serum CRP, and ferritin values each had a relation with the serum ALP activity. Fluid ALP concentration of RA was 110.3 +/- 40.1 IU/L, and that of OA, 83.6 +/- 15.0 IU/L (P < 0.05), respectively. In RA, a predominant isozyme was liver-type one both in the sera (91%) and the synovial fluid (59%). However, this result means that bone-type one was more abundant in the synovial fluids (41%) than those in the sera (9%). An enzymehistochemical and an immunohistochemical studies revealed that ALP was positive in a perivascular area, sublining cells, and a part of vascular endothelium in RA. In contrast, the synovial tissue from OA and a healthy patient exhibited only a weak staining. In RA, a positive correlation between the elevation of serum ALP and the disease activity was confirmed. Furthermore, we elucidated that ALP is produced in RA synovium.

[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.

[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.