A rabbit osteoarthritic knee model was used to analyze time-related accessibility of high molecular weight 2,700 kDa hyaluronan to healthy and osteoarthritic articular cartilage and synovium.
    Fluorescein-labeled high-molecular weight 2,700 kDa hyaluronan (F-HA) was found in shallow, inner and deep layers of degenerated cartilage within 3-24 h after injection. It quickly reached the deep cartilage layer and was retained within inner and deep layers up to day 28.
    In constrast, in healthy knees, F-HA accessibility was confined to superficial and shallow cartilage layers during 3-24 h and did not change until day 28, showing no signs of deep layer retention.
    In both healthy and osteoarthritic knees, F-HA penetrated synovium from its synovial lining cell layer to the interstitium in subsynovial fat tissue (deep layer) at 3-24 h after injection.
    Though having a high molecular weight, 2,700 kDa HA rapidly penetrated shallow, inner and deep layers of degenerated cartilage and deep layer of synovium after its intra-articular injection.
    The joint tissue penetration of 2,700 kDa HA after its intra-articular injection in an animal OA model indicates that soon after the injection, hyaluronan is rapidly accessible to synovial and degenerated cartilage tissues. There, it exerts its anti-inflammatory actions on the synovium and degeneration-inhibiting action on the articular cartilage.

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［Objective and Methods］
    Associations among sleep disorders, depression, anxiety, and pain were investigated in 240 cases among 190 patients(mean age 58 years at the time of survey; 22 males and 168 females) diagnosed with RA based on the diagnostic criteria established by the American College of Rheumatology (ACR) in 1987.
［Results］
1)Incidence of depression: In the first survey of the190cases using CES-D, a depression was noted in 45 cases (24%), when scores of 16 points or higher were regarded as indicating depression.
2) Relationships between the presence or absence of depression: state and trait anxieties and VAS were significantly higher in cases with depression than in those without.
3)When the sleep latency (time to fall asleep) was classified into periods within 15 minutes and those 15 minutes or longer, the incidence of depression and the state and trait anxiety and VAS scores were significantly higher in cases showing a 15-minute or longer sleep latency.
4) Depression scores (CES-D) was significantly higher in cases showing intermittent awakening during sleep (nocturnal wakening) than in those without such awakening.
5) Early awakening: The incidence of depression was markedly higher in patients who awoke earlier than 4:00 (6/9 patients, 66.7%). Moreover, depression and both anxiety scores were significantly higher in patients who awoke before 4:00 compared with others who awoke after 4:00, but no significant difference was noted in VAS.

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    Bucillamine is a disease modifying antirheumatic drug (DMARD), developed in Japan and widely used for more than 20 years. As the bucillamine molecule contains two SH radicals, it is unstable in the presence of water, causing an offensive smell or discolouration. Bucillamine went out of patent in 1988, and 6-generic products have been released in Japan. All the generic products have passed quality reevaluations by the Japanese Ministry of Health, Labour and Welfare, although no long-term stability testing has been conducted.
    Sugimoto et al. conducted a 6 month accelerated stability trial of the original product and 4 generic products, finding decreased solubility and drug content in some of the generic products (Diagnosis and Treatment 2000; 88: 1940-3).
    In this study, we conducted stability testing of 7 bucillamine preparations, comprising the original product and 6 generic products, in the final packaging, press through packing (PTP) and the unpackaged state, with the purpose of assessing the stability of these products up until they are taken by the patient. Our results showed that the original product and 2 of the generic products were stable under all conditions tested, but decreased solubility and drug content were seen in the remaining generic products. An unpleasant smell could be detected immediately upon removing the samples that had deteriorated over time from their packaging. Further quality evaluation using long-term storage studies are therefore required for these generic bucillamine preparations.

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    We performed single dose mizoribine (MZR: immunosuppressive drug) treatment with high daily concentration for patients with rheumatoid arthritis (RA). This clinical trial was performed on 18 RA patients (4 Male, 14 Female. Age 33-81. Duration 1-15 years. StageI: 5, III: 1, IV: 12. Class2: 13, 3: 4. Disease Activity Score: DAS 28＝5.0＋/－1.3) with complications and/or some drugs refractory stage in Kinki University School of Medicine over six months. Finally, five of the 18 RA patients improved in not only clinical data on the DAS 28＝3.7＋/－0.9 and personal comfortableness but also decreased steroid dose and other drugs. Another five RA patients continued the trial but remained unchanged (DAS 28＝4.3＋/－1.0), and eight RA patients discontinued the trial: three were unchanged (DAS 28＝5.1＋/－0.7), three were personal dropout (DAS 28＝6.1＋/－1.0), one was side effect (oral erosion on 3 months later) and one was worse. Five of the eight dropout RA patients used biologics after this trail. The effectiveness of single dose mizoribin treatment for RA patients was demonstrated one of the effectiveness in this study.

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Objective: To compare the ACR and the EULAR response criteria in RA patients treated with infliximab.
Methods: Two rheumatologists evaluated 33 patients with RA who were injected IFX more than 5 times. Tender joint count, swollen joint count, physician global assessment, patient assessment of pain, patient global assessment, patient assessment of physical function, and C-reactive protein (CRP) were examined just before each IFX injection.
Results: The achievement rates of the ACR response gradually elevated after the start of IFX treatment, while the achievement rates of the EULAR response plateaued just after the second IFX injection. The ACR response was worse than the EULAR response throughout the observation periods. The 20%-achievement rates of patient assessments of global and physical function in the high disease activity group (having 6 or more tender and swollen joints and CRR level 2 mg/dl or more) were around 20% higher than those in the low disease activity group. The ACR response was affected by the disease activity at the baseline, while the EULAR response was not. Patient assessments had relatively wide variation (noise) compared to improvements (signal) that may cause the invalidity of the ACR response.
Conclusion: The EULAR criteria responded more rapidly than the ACR criteria. The ACR response was poor compared to the EULAR response especially in the low disease activity group.

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Objective: The goal of this study was to determine the effect of etanercept in patients for whom infliximab failed.
Methods: A total of 116 biologically naïve patients with RA (naïve group) and twenty-five patients with RA for whom infliximab failed were treated with etanercept (switching group). Kaplan-Meier survival curves, Disease Activity Score in 28 joints (DAS28), and prednisolone were evaluated at base line, 1, 2, 3, 6 and 9 months after etanercept treatment started.
Results: 58 to 73 percent of patients in the switching group achieved either a moderate or good European League Against Rheumatism (EULAR) score at each point. With regard to continuation rates, there was no difference between the switching group and the naïve group. With regard to moderate or good EULAR scores, there was no difference between switching group and naïve group, except the naïve group was higher than the switching group at 9 months. With regard to decreased rates of prednisolone, the naïve group had a greater decrease than the switching group at 1 month, 2 months and 3 months, respectively. The reasons for stopping etanercept are not related to the reasons for stopping infliximab.
Conclusion: Etanercept is as effective in patients for whom failed infliximab as same as in biologically naïve patients.

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Objective: We studied the effect and safety of bi-weekly 25 mg etanercept (ETN) in the system of combination therapy in which an administration of immuno-suppressive medicine is added to the current immuno-suppressive treatments.
Methods: 28 patients with rheumatoid arthritis (RA) (7 males, 21 females) were studied. The patients were already given methotrexate (MTX) and/or tacrolimus (TAC) more than 3 months before the start of 25 mg ETN bi-weekly administration. They were followed for more than 24 weeks.
Results: At 24 weeks, 22 cases were continuously given bi-weekly 25 mg ETN, while 5 cases were changed to weekly administration and one case stopped due to the patient’s wishes. The dose of MTX was raised in one case at 8 weeks, and TAC in another case at 18 weeks. Averages of CRP, MMP-3 and DAS28 (CRP) at ETN start/24 weeks were 2.69/1.41, 355/249 and 4.56/3.35, respectively. Assessment of effectiveness using DAS28 (CRP) were Good: 11, Moderate: 9, No: 8 cases at 24 weeks. The distribution of disease activity by DAS28 (CRP) were as follows: 20 high cases, 7 moderate cases and 1 low case at start; 7 moderate cases, 3 low cases, 10 cases of remission, and another 8 cases classified as failure of bi-weekly 25 mg ETN (6 cases were changed to weekly administration, 2 cases were the dose of MTX/TAC raised) at 24 weeks. One serious adverse event of pneumonia was observed, but the patient recovered without hospitalization.

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    A 37 year-old woman with overlapping syndrome of dermatomyositis (DM) and rheumatoid Arthritis (RA) visited to my office as having RA. At the first visit, as 10 mg of prednisolone/day, 1000 mg of salazosulfapirizin/day and 6 mg of methotrexate/week were already being administrated, treatment of RA begun. As the first blood examination showed positive rheumatoid factor and the abnormality of liver function, we added 2 mg of folic acid considering the side effects of MTX.
    After that, increased enzymes derived from muscle were found. 4 months later, she was admitted to Oita Red Cross Hospital because muscle enzymes had increased much. That blood examination revealed that anti-nuclear antibody and anti-Jo1 antibody were positive. Finally, she was diagnosed with overlapping syndrome with RA and DM. The case of simultaneous onset of RA and DM usually goes through a serious clinical course with lung fibrosis. However, this case was treated with a small dose of PSL (30 mg/day) and 1.5 mg of Tascrorims, resulting in easier remission without lung fibrosis.
    Since the first visit to my office, she was presented Gottoron’s sign, Heliotrope rash, and poikiloderma retrospectively.
    Preconception for RA induced the misjudgment of the right diagnosis. The wrong diagnosis was made partly because the anti-nuclear antibody was not examined at the first medical examination.
    When there are doubts about RA in the first medical examination, it is necessary to examine the antinuclear antibodies from the first visit.

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    In the era of biologic disease modifying anti-rheumatic drugs (DMARDs) such as infliximab (IFX) for rheumatoid arthritis (RA), we have very strong weapons to control RA. However, severe adverse effects such as reactivation of tuberculosis should be considered especially in early period of the treatment.
    A 49-year-old man, who had been in very high disease activity of RA ever with 8 mg/week of Methotrexate (MTX) and 7 mg/day of prednisolone, had been treated with IFX for 33 months and isoniazid (INH) as prophylaxis for tuberculosis. Although he had been in good control or remission state of RA, he was admitted because of right pleural effusion. In spite of negative result of tuberculosis culture, his effusion was completely responded with anti-tuberculosis agents. So tubercular pleuritis was strongly suggested. Then, his RA activity had been very high active state.
    As early reactivation of tuberculosis by IFX was prevented with INH, we wondered that late onset of tuberculosis should be considered in patients with RA under the treatment of IFX. And the other prophylaxis or the early diagnosis of tuberculosis could be reviewed for later phase of IFX.

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    The patient was a 34-year-old male. He visited our hospital for erythema, livedo reticularis,and arthralgia in November 2005.Skin biopsy revealed necrotizing vasculitis and a diagnosis of cutaneous polyarteritis nodosa (CPAN) was made. In March 2008, he was admitted to our hospital for myalgia in the left upper arm.
    There was an elevation of CRP but no rise of myogenic enzymes on admission. Autoantibodies, such as rheumatoid factor, antinuclear antibody, and anti-neutrophilic cytoplasm antibody were not detectable. Gadolinium ―enhanced MRI of the left upper arm showed an irregularity in the middle collateral artery and patchy areas of high intensity along the middle collateral artery in the triceps brachii muscle. These findings were considered to reflect vasculitis of CPAN and secondary edematous changes of the muscle. The patient was successfully treated with corticosteroids and MTX before being discharged. Gadolinium-enhanced MRI is useful to diagnose muscular lesions associated with vasculitis.

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