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Aim: Based on the benefit/risk profile of combination therapy with methotrexate (MTX) and Infliximab (IFX), a lower dosage of MTX might be preferable if IFX efficacy can be maintained.
Objectives: We evaluated whether MTX could be tapered to the minimum dosage (2 mg/week) in patients with rheumatoid arthritis (RA) who achieved adequate response to combination therapy. In addition, we evaluated whether adding low-dose tacrolimus (TAC) is efficacious for patients showing inadequate response to the therapy.
Method: Subjects comprised 51 RA patients who had received the combination therapy for ≥22 weeks. To analyze clinical response, disease activity score 28 using C-reactive protein (DAS28-CRP) was used to judge response to IFX. In patients with adequate response (DAS28≤3.2), MTX tapering was initiated by 2 mg every 8 weeks. In patients with inadequate response (DAS28＞3.2) to therapy at entry, TAC was added (maximum,2 mg/day).
Results: Thirty patients were enrolled and 21 patients (70%) with adequate response to therapy underwent reductions in MTX dosage. Sixteen of 21 patients maintained good response despites the mean dosage of MTX being reduced from 7.18 to 2.50 mg/week over 32 weeks. All patients with short disease duration (＜5 years) or with Steinbrocker class I could maintain good clinical response despite of MTX tapering. Nine inadequate-responders to IFX received added low-dose TAC, and clinical response improved in only 3 patients. Addition of low-dose TAC appears few efficacious.
Conclusion: Seventy six percent of the patients with adequate response to combination therapy with MTX and IFX achieved DAS28≤3.2 while reducing the mean MTX dose to 2.50 mg/week.

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Objective: Recently, the number of rheumatoid arthritis (RA) patients treated with anti-tumor necrosis-α (anti-TNF-α) has been rapidly increasing. At present, however, there are no available measures that can serve as an indicator of its efficacy. Anti-cyclic citullinated peptide Antibody (anti-CCP antibody) wasconsideredto be an importantprognostic factor atAmerican College of Rheumatology (ACR) recommendation in 2008. And anti-CCP antibody has the possibility to be able to become an important prognostic factor in anti-TNF-α therapy.
Methods: In view of the above, we investigated the relationship between the efficacy of infliximab (IFX) and anti-cyclic citullinated peptide antibody (anti-CCP antibody). IFX was administered to 38 patients with RA during the period from 2006 to 2010,with those having initial anti-CCP antibody levels of less than 100 U/ml referred to as Group A and those having initial anti-CCP antibody levels of 100 U/ml or more referred to as Group B. We investigated the effectiveness of IFX for clinical joint symptoms by comparing the groups in C-reactive protein (CRP), Visual analogue scale (VAS), and disease activity score in 28 joints (DAS28), matrix metalloproteinase (MMP)-3 and adherence at week 0, week 6, week 14, and week 22.
Results: The CRP levels of group A was significantly lower that that of Group B at week 0, week 6, and week 22. No other significant parametric differences were recognized between the two groups. To compare the items of interests at week 0 and week 22, Group A exhibited significant improvements in all items except MMP-3, whereas Group B made no significant improvements in the number of tender joins and swelling joints, ESR, and MMP-3. Additionally, while anti-CCP antibody levels significantly improved in IFX responders (good response＋ moderate response in EULAR criteria) between week 0 and the last observation, non-responders showed no significant reduction in anti-CCP antibody levels.
Conclusion: These results suggest that the group with initial anti-CCP levels of 100 U/ml or more may respond poorly to IFX compared to initial anti-CCP levels of less than 100 U/ml and that anti-CCP antiboy may be significantly lower in responders.

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Objective: Infliximab (IFX), a monoclonal antibody against tumor necrosis factorα (TNF-α), has been used for the treatment of rheumatoid arthritis (RA). However, some patients report a decrease in the effectiveness of IFX therapy during the course of the treatment. In July 2009, dose escalations and interval shortening of IFX infusion were approved in daily practice. We evaluated cases that required IFX dose escalation and/or interval shortening.
Material and Method: We selected 124 patients (23 men and 101 women; median age, 56 years; age range, 24-81 years) who were treated with IFX for RA. The median of the total number of IFX infusions received was 17 (range, 4-51 times). We evaluated the cases that required dose escalation and/or interval shortening of IFX infusion.
Results: Of the 124 cases, 42 cases (33.9％) required dose escalation and/or interval shortening. Of these 42 cases, 14 required dose escalation; 15, interval shortening; and 13, both dose escalation and interval shortening. No serious adverse events were observed in any case. Despite these measures, 8 cases did not respond well.
Conclusion: IFX dose escalation and/or interval shortening were carried out in patients in whom IFX treatment was less effective. A recovery of the effectiveness of IFX treatment was observed in 33 of the 42 cases (78.6％). Therefore, dose escalation and/or interval shortening are effective procedures in patients in whom a reduction in the effectiveness of IFX treatment is observed.

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Objectives: Patients with rheumatoid arthritis (RA) were treated with etanercept (ETN) using different dosage regimens, and the differences in the clinical effects and complications were examined.
Subjects and methods: Seventy-two patients who received ETN therapy at our hospital were divided into 3 treatment groups: Group A, which received continuous administration of ETN 25 mg twice every week (n＝36); Group B, which received weekly administration of 25 mg (n＝24); Group C, which received weekly administration of ETN 25 mg, the treatment then stepped up to twice every week (n＝12). Background factors at the start of ETN therapy, including the mean age, RA duration, MTX dose, PSL dose, and clinical indicators (DAS-CRP, CRP, and serum MMP-3), were compared among the groups, and variations in these indicators before versus after ETN therapy were investigated.
Results: There were no significant differences in the age, RA duration, MTX dose, PSL dose, serum CRP, MMP-3, or DAS-CRP among the three groups. The remission rate at Week 24 based on the DAS28/CRP was highest in Group B (29.4%). Nine patients discontinued administration, 6 due to bacterial infections as adverse events. The persistence rate obtained by the Kaplan-Meier method at Week 52 was highest in Group A (83%).
Conclusions: The clinical effects obtained at Week 24 did not differ between once weekly and twice weekly administration of 25 mg ETN. The percentage of patients who discontinued administration due to the onset of complications tended to be slightly higher in the group receiving once weekly administration (Group B).

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    The aim of this retrospective study is to compare clinical efficacy of adalimumab (ADA) administered as first biologics (NG: n＝125) with that administered as second or third biologics (SG: n＝75) and to compare the efficacy of ADA switched from infliximab (IFX) with that switched from etanercept (ETN). Data was collected from 21 institutions in total. DAS28-ESR, EULAR criteria, serum CRP, serum MMP-3 and drug continuation rate (Kaplan-Meier method) were evaluated. There were no significant differences in baseline characteristics between NG and SG. Mean DAS28-ESR in NG and SG at 24 weeks were 3.84 and 4.40 (p＜0.05), respectively. Rate of remission evaluated by EULAR criteria at 24 weeks in NG and SG were 29.3% and 17.8%, respectively. Mean CRP at 24 weeks in NG and SG were 1.31 mg/dl and 1.90 mg/dl, respectively. Mean MMP-3 at 24 weeks in NG and SG were 215.2 ng/ml and 262.0 ng/ml (p＜0.05), respectively. Drug continuation rate in NG was significantly better than that in SG. Clinical outcomes of ADA switched from IFX were better than that switched from ETN, especially in drug continuation rate, EULAR response and MMP-3. In conclusion, efficacy of ADA in NG was better than that in SG and efficacy of ADA switched from IFX was better than that switched from ETN in clinical practice.

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Objective: Results of long-term adalimumab (ADA) treatment were investigated including a radiologic evaluation.
Subject and methods: The subjects were 56 RA patients (14 males and 42 females with a mean age of 61.4 years) that had received ADA treatment for at least 2 years after the initiation of treatment, and 39 of whom had switched from other anti-TNF drugs while 17 did not administer any anti-TNF drug. ADA was subcutaneously administered for two weeks. The clinical evaluation was performed at 4,8,12,16,24,52, and 104 weeks after the initiation of treatment using the EULAR improvement standards (DAS28CRP). At 2 years after the initiation of treatment, functional and radiographic evaluations were performed using the MHAQ and sharp score methods.
Results: Of the 56 patients, 22 continued ADA treatment for 2 years, and both DAS28CRP and plasma MMP-3 concentrations decreased significantly in 2 years. The discontinued cases were 25 patients due to poor response or secondary failure,5 due to adverse drug reactions, and 4 due to their personal circumstances.
    In the functional evaluation of the 22 patients that continued the treatment for 2 years, using MHAQ, significant improvement was obtained and even the radiographic evaluation revealed inhibition of bone joint degeneration particularly in the good response group (14 patients).Conclusion: Among the patients whose disease activity was inhibited by ADA, clear improvement was seen in the functional and radiologic evaluations after two years.

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Objective: We investigate the optimal clinical use of Adalimumab (ADA) for RA patients who resisted prior DMARDs therapy.
Patients and methods: In 2009-2010, 55 RA patients were treated with ADA for 24 weeks in Kinki University RA groups (open label and multi center).
Results: At 24 weeks, we evaluated 53 RA patients to find good response 14 (26%), moderate response 25 (in total 73.6%), unchanged or poor 9,unevaluated 5. The final remission rate increased the DAS to 22.4% and CDAI to 19.0%.In the LOCF analysis, DAS 28 decreased from 5.23 to 3.66.Clinical results were good in Bio naïve and MTX combination groups.
Conclusion: The optimal uses of ADA for RA treatment, are bio-naïve cases and using with the MTX.

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Objective: Over the last decade, the treatment of rheumatoid arthritis (RA) has changed considerably. Biologic agents, in particular, have greatly improved the quality of life of RA patients. However, there are many effective drugs in general use; therefore, RA patients may not obtain correct information regarding the treatment and care of this condition. At the request of the Gifu prefecture branch of the Japan Rheumatism Friendship Association, we have held this annual lecture at the university hospital since 2008. The meeting is held in April every year. At the fourth meeting this year, we evaluated the proceedings and the opinions of the participants.
Results: The number of participants for each year from 2008 to 2011 was 100, 75, 90, and 75, respectively. The lectures were presented by a rheumatologist, a clinical laboratory technologist, a pharmaceutical chemist, a social welfare counselor, and a clinical nurse specializing in rheumatology. Questionnaires about the meeting were evaluated, which revealed the various opinions of the participants. Positive opinions included the following: The lectures helped me to resolve my concerns about drugs for RA. I will endeavor to maintain a positive attitude after talking to the other RA patients. On the other hand, some participants found the content of the lectures difficult to understand.
Conclusion: We will continue to conduct informative meetings to educate RA patients. We believe that these activities will help RA patients to improve their quality of life.

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    We experienced two cases with rheumatoid arthritis which were diagnosed as pneumonia during tocilizumab treatment. Both cases showed clear symptoms such as general fatigue (case 1), coughing, and sputum (case 2). One patient (case 1) had an increased fever, but the other (case 2) did not. C-reactive protein showed negative on admission probably because of the effect of tocilizumab. However, white blood cells and the proportion of neutrophils were highly upregulated compared with those before the onset of pneumonia, suggesting that these findings were helpful for the diagnosis of bacterial pneumonia. Both cases showed a flare-up of disease activity and one (case 1) was treated with tocilizumab again while the other (case 2) was switched to etanercept.

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    A 43-year-old man presented polyarthralgia, malar rash, and low-grade fever, proteinuria, lymphocytopenia and positive ANA. He was diagnosed as systemic lupus erythematosus and admitted to our hospital for further evaluation. On admission, laboratory findings revealed proteinuria (1.9 g/day), hepatic disorder, positive immune complex, and negative anti-DNA. Serum anti-ribosomal P protein antibodies (anti-P) were markedly elevated. Findings of renal biopsy were consistent with ISN/RPS class V nephritis, with deposition of IgG and complements in the glomeruli. The absence of anti-DNA suggest that anti-P might be involved in the development of lupus nephritis in our patient.

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[in Japanese]

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    Early diagnosis and early treatment are most important for inducing remission of rheumatoid arthritis. The sensitivity and specificity of the different diagnostic and classification criteria were compared in a retrospective study using 104 patients with arthritis. The results indicate that 2009 ACR/EULAR criteria and Japanese Health and Welfare Ministry criteria are very useful for early diagnosis because of their high sensitivity and specificity, while 1987ARA and 2010ACR/EULAR criteria with low sensitivity are not suitable. X-ray examination, especially HRR (High Resolution Radiograph), but not serological tests, is a more important tool for early diagnosis. The review of the management guidelines in an experience based survey of about 2000 patients with RA revealed significant problems in Japan with the dose limitation of MTX and the high cost for patients to receive biologics. As JCR guidelines for treatment with biologics recommend, biologics have to be considered if there is the progressive erosion on imaging examination after DMARDs therapy for 3 months. However, there are many patients in remission only using non-biological DMARDs. The tight control of RA by monitoring with imaging such as HRR is the best method of management to stop joint destruction.

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    Although disease modifying antirheumatic drugs (DMARDs) have been the mainstay of pharmacotherapy for rheumatoid arthritis (RA) since the 1980s, the clinical introduction of biological agents has seen a paradigm shift in the field of rheumatology. The aim of treatment has changed from reduction of pain and inflammation to disease remission. Biological agents are not a boon to all RA patients, however, and there are problems with high cost, safety, nonresponse, etc. Other problems with pharmacotherapy in general need to be addressed. 1) When should biological agents be introduced? 2) Can treatment be stopped once remission has been achieved? How should we manage patients after ceasing biological agents? 3) When do we use DMARDs versus biological agents? 4) Should DMARDs be used as monotherapy or in combination?
    We conducted a clinician-directed clinical trial (JaSTAR study), with the collaboration of “Society of Japanese Rheumatologists in Private”, in which we compared triple combination DMARDs therapy and biological agent therapy in the treatment of RA, based on the U.S.TEAR study. In this paper, we will present a review of the literature, as well as a discussion of what RA patients really want from their treatment, and future directions in the pharmacotherapy of RA.

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    A recent topic in treatment targeting rheumatoid arthritis (RA) is treatment with biologics in RA. However, painful joints still remain even in cases of remission. We tend not to be aware of painful joints in movement besides resting pain. From a functional perspective, range of motion (ROM) in RA joints is important reflecting HAQ scores in the upper limbs. Arthroscopic synovectomy is useful for improving ROM in upper limbs by removing fibrous tissue filling in joint cavities and capsular release is useful for providing ROM. In progressive joint destructionand deformity of the hand, arthroplasty and ligamentous tightness are useful after adequate rehabilitation. Surgical application for improving the function of upper limbs not only eliminates pain but also provides ROM of joints especially in effective treatment by systemic biologics. Japanese rheumatologists are noted world wide for their arthroscopic surgery for improving the function of joints and the development of this field is expected to ensure quality remission.

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[in Japanese]

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[in Japanese]

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