Masakazu Nagashima

An intronic SNP in a RUNX1 binding site of SLC22A4 , encoding an organic cation transporter, is associated with rheumatoid arthritis

Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

Changes in coagulation-fibrinolysis marker and neutrophil elastase following the use of tourniquet during total knee arthroplasty and the influence of neutrophil elastase on thromboembolism

Background:  To clarify in detail the mechanism underlying the development and exacerbation of deep venous thrombosis (DVT) and/or pulmonary thromboembolism (PTE), we focused on the following factors: the thrombin‐antithrombin III complex (TAT), D‐dimer and neutrophil elastase (NE). We basically investigated whether NE played an important role in the development of PTE I a mice model.

Comparative study between thromboembolism and total knee arthroplasty with or without tourniquet in rheumatoid arthritis patients.

Abstract Introduction. To investigate whether the occurrence of pulmonary embolism (PE) and/or deep vein thrombosis (DVT) are influenced by use of a tourniquet or not in the patients who underwent total knee arthroplasty for rheumatoid arthritis (RA). Patients and methods. The patients were randomly divided into a with-tourniquet group (19 patients) and a without-tourniquet group (18 patients). In the first group, snowstorm-like echogenic particles were observed after deflation of the tourniquet in all patients according to the transesophageal echocardiography. Results. In addition, the PaO2 level was significantly decreased. Also, one had a PE, and DVT was confirmed in two patients. In the without-tourniquet group, none of these conditions was noted. Conclusion. These results suggest that the use of a tourniquet will promote the risk of developing postoperative PE and/or DVT after total knee arthroplasty.

Study of the Mechanism Involved in Angiogenesis and Synovial Cell Proliferation in Human Synovial Tissues of Patients with Rheumatoid Arthritis Using SCID Mice

To examine whether synovial cell proliferation is due to angiogenesis, we studied the relationship between the inhibition of synovial cell proliferation and an angiogenesis inhibitor, TNP-470, in human synovial tissues. Human synovial tissues were implanted into the back of SCID mice (SCID-HuAg mice). Sixteen mice were divided into two groups of eight mice each: the untreated group (vehicle group) and the TNP-470-treated group that received a dose of 10 mg/kg body weight by subcutaneous injection. The number of blood vessels and synovial lining cells clearly increased in the vehicle group, but the number of synovial lining cells clearly decreased and the blood vessels were hardly detected in the TNP-470 group. Immunohistochemically, cells that stained positively for the anti–proliferating cell nuclear antigen (PCNA) mAb were abundant in synovial lining cells and endothelial cells in synovial tissues. Cells that stained positively for the anti-CD34 polyclonal antibody were abundant in the endothelial cells in the vehicle group, but these positively stained cells were hardly detected in the TNP-470 group. The PCNA positivity ratio in the vehicle group was 0.64 ± 0.019, whereas that in the TNP-470 group was 0.199 ± 0.007. The numbers of cells that stained positively for anti-CD34 polyclonal antibody were 242 ± 13.4 in the vehicle group and 153 ± 6.73 in the TNP-470 group per 10 microscopic fields. Cells that stained positively for anti-mouse CD31 mAb were mainly localized in the synovial lining, but invaded the subsynovial lining layer in human synovial tissues. On the other hand, cells that stained positively for anti-human CD31 mAb were mainly localized in the subsynovial lining layer. We found that endothelial cell proliferation is dependent on angiogenesis based on the result that angiogenesis and synovial cell proliferation were inhibited by treatment with TNP-470.

Granulocyte and monocyte apheresis suppresses symptoms of rheumatoid arthritis: a pilot study

Abstract To investigate if granulocyte and monocyte apheresis mitigates the symptoms of rheumatoid arthritis (RA), and influences production of panmyelocytes (CD15+ CD16– cells) at the bone marrow level, 27 RA patients who had elevated granulocyte counts were recruited. The granulocyte and monocyte apheresis column (G-1 column) is an extracorporeal type device packed with 220 g cellulose acetate beads to which granulocytes and monocytes specifically adhere. Patients received apheresis of 1 hr duration twice per week, 8 times over a period of 4 weeks. To prepare CD15+CD16– cells, iliac bone marrow aspirate was obtained at baseline and at 2 weeks after completion of the apheresis course. Ex-vivo proliferation of bone marrow low density cells and production of IgM-RF were also investigated. Following granulocyte and monocyte apheresis, there was a suppressed tendency in the number of CD15+CD16– cells in patients with high bone marrow CD15+CD16– cell counts at baseline. Clinical assessments 2 weeks after the completion of apheresis therapy showed improvements in swollen joint count (P<0.001), tender joint count (P<0.001) and duration of morning stiffness (P<0.005). The results suggest that granulocytes and monocytes/macrophages have a pathological role in RA and apheresis treatment to reduce or suppress these cells should benefit patients with RA.

The anti-rheumatic effect of multiple synovectomy in patients with refractory rheumatoid arthritis

Abstract We assessed the anti-rheumatic effects of radical multiple synovectomy (RaMS) in patients with rheumatoid arthritis (RA) who did not respond to intensive medical treatment. The selection of patients into three groups, A, B or C, was randomised. Patients assigned to group A (n=28) continued the prescribed pre-operative medication and had RaMS. Patients assigned to group B (n=20) were started on a combination therapy with disease-modifying anti-rheumatic drugs (DMARDs) after radical multiple synovectomy. Nineteen RA patients who were started on the same combination therapy as group B but who did not undergo surgery served as controls (group C). The clinical and radiographic findings were assessed for at least 3 years after surgery. Patients in the surgically treated groups (groups A and B) showed a significant reduction in the number of swollen and painful joints and in their ESR and serum CRP levels, and this effect was maintained for at least 3 years. More than 40% of the patients remained in clinical remission during the observation period. The surgical outcome seemed to be superior to that of the controls and did not differ between group A and group B. Articular destruction (assessed by the carpal height ratio) did not progress in the patients who were in clinical remission.Résumé Nous avons étudié les effets anti-rhumatoı¨de de la synovectomie complète multiple dans trois groupes de patients atteints d’arthrite rhumatoı¨de réfractaire au traitement médical. La sélection des patients en trois groupes a été faite au hasard. Les patients du groupe A (n=28) ont continué le traitement pré-opératoire prescrit; ceux du groupe B (n=20) ont commencé, après l’intervention un traitement par médicaments anti-rhumatismaux. Enfin 19 patients qui ont commencé la même combinaison thérapeutique que le groupe B mais sans intervention chirurgicale ont servi de groupe de contrôle. Les patients ont été suivis au moins 3 ans après le traitement chirurgical. Les patients traités par synovectomie ont montré une réduction du nombre d’épanchement, de douleurs articulaires ainsi qu’une diminution de la vitesse de sédimentation et du niveau de la CRP ceci s’étant maintenu pour au moins 3 ans. Plus de 40% des patients sont restés en rémission clinique durant la période d’observation. Les destructions articulaires mesurées par la hauteur du carpe n’ont pas progressé pendant la période de rémission.

Expression of κ-opioid receptor mRNA in human peripheral blood lymphocytes and the relationship between its expression and the inflammatory changes in rheumatoid arthritis

Abstract The expression of the κ-opioid receptor on human peripheral blood cells (in rheumatoid arthritis cases and normal volunteers) was examined using reverse transcriptase polymerase chain reaction (RT-PCR), and the relationship between its expression and the inflammatory activity or chronic pain in patients with rheumatoid arthritis (RA) was determined. RT-PCR was performed on the peripheral blood cells obtained from 37 patients with RA and 13 healthy volunteers. κ-Opioid receptor mRNA expression was exhibited on the blood cells of 37% of RA patients (14/37) and 54% of healthy volunteers (7/13) , and the levels of expression were lower in the RA patients than in the healthy volunteers. Regarding the relationship between the expression of κ-opioid receptor mRNA and the symptoms in RA patients, it was noted that the expression of the receptor mRNA was significantly decreased in RA patients in whom erythrocyte sedimentation rate (ESR), Lansbury index, and visual analogue pain scores were high. The κ-opioid receptor mRNA was expressed on four cell types, namely, T and B cells, macrophages, and natural killer (NK) cells in RA patients; however, it was expressed only on the T and B cells and macrophages (and not on NK cells) in the healthy volunteers. Our findings suggest that the levels of expression of κ-opioid receptor mRNA were decreased in RA patients in comparison with those in healthy volunteers; and that they were significantly related to the inflammatory activity or chronic pain in the RA patients. The higher the mRNA expression level, the less severe the inflammatory changes of RA. The κ-opioid receptor may thus play a role in the modulation of nociception and anti-inflammatory changes in chronic inflammatory disorders.

A modified Hohmann method for hallux valgus and telescoping osteotomy for lesser toe deformities in patients with rheumatoid arthritis

To preserve the function of metatarsophalangeal joints and to ensure forefoot stability in patients with rheumatoid arthritis (RA), we performed a modified Hohmann method for hallux valgus (HV) and telescoping osteotomy of lesser toe deformities instead of fusion of HV or resection of all metatarsal heads. From October 1995 through March 2001, 47 RA patients (90 feet) with severe HV and forefoot deformities were examined. The indication for the procedure in all the patients was disabling foot pain secondary to intractable plantar callosities below the lesser metatarsal heads, painful HV deformities, and the severe deviation of the sesamoid complex diagnosed by the basis of X-ray images. The HV and intermetatarsal (M1M2 and M1M5) angles and sesamoid complex were measured on the preoperative and postoperative roentgenograms. According to the results of a questionnaire survey, the patients were divided into three groups using the visual analogue scale; group 1: satisfied, group 2: fair and or no pain, group 3: dissatisfied. HV and M1M2 angles significantly improved compared between pre- and postoperative or preoperative and the follow-up periods. Out of the 47 patients, 78.9% were satisfied with the results of the operation and 8.9% were dissatisfied. Of these patients, 12.2% reported fair results. There were several complications, such as painful callosity, which was recurrent in seven feet, and delayed wound healing was observed in two out of 90 feet. A modified Hohmann method and abductor hallucis correction are effective in relieving pain and ensuring the bony union of the great toe in spite of severe osteoporosis.

Leflunomide-induced polymyositis in a patient with rheumatoid arthritis

Although rheumatoid arthritis (RA) and myositis are major autoimmune diseases, co-occurrence of the two is rare. We treated a patient who developed polymyositis (PM) following the treatment of RA with leflunomide. Prednisolone (PSL) in combination with methotrexate (MTX) was effective in managing the PM, but the RA relapsed during the treatment. Based on the clinical course, we suspect that the PM was induced by the leflunomide treatment and suggest that clinicians should consider the possibility of this rare adverse event in cases of cholestyramine-resistant elevation of transaminases.

Granulocyte adsorptive apheresis for leg ulcers complicated by rheumatoid arthritis: a report on three successfully treated cases

Background  The treatment of inflammatory leg ulcers complicated by rheumatoid arthritis (RA), which are unresponsive to conventional care, can be frustrating. Furthermore, as granulocytes and monocytes (GM) are major sources of inflammatory cytokines, they have the potential to initiate and perpetuate inflammatory skin lesions. Accordingly, a recent study reported the remission of pyoderma gangrenosum following the reduction of activated peripheral blood GM by adsorptive apheresis (GMA).