Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: A Japanese multicentre investigational study (ORIGAMI study).

OBJECTIVES: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan. METHODS: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry. RESULTS: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively. CONCLUSIONS: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting.

Investigation of clinical characteristics as predictive factors for the humoral immune response to the influenza vaccine in patients with rheumatoid arthritis.

The objective of this observational study is to determine characteristics as predictive factors for the humoral immune response to the influenza vaccine in patients with rheumatoid arthritis (RA). Fifty-seven RA patients who visited our department between 2011 and 2012 were recruited for the present study. The anti-influenza antibody titers of a trivalent influenza subunit vaccine (A/California/7/2009 (H1N1)-like strain (A/H1N1 strain), A/Victoria/210/2009 (H3N2)-like strain (A/H3N2 strain), and B/Brisbane/60/2008-like strain (B strain)) were measured at baseline and 4 weeks after the vaccination using the hemagglutination inhibition assay. Associations between the immune response to the influenza vaccine and clinical characteristics such as background, clinical parameters, and "having treatments or not" were examined to determine predictive factors for the immune response to the influenza vaccine. The titers of the three strains were significantly increased in all RA patients after the influenza vaccination. Concerning predictive factors of the immune response, no significant differences were observed in background (age and sex) or clinical parameters (peripheral lymphocyte count, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, matrix metalloproteinase-3, and disease activity score-28). No significant differences were observed in the titers of anti-influenza antibodies between the treatment (methotrexate, prednisolone, salazosulfapyridine, or tacrolimus) and no-treatment groups. In contrast, there was a significant difference in A/H3N2 strain between the patients with biologics and without biologics. The only factor that affected anti-influenza antibody titers was "having biologics or not"; therefore, the immune response to the influenza vaccine may not be predicted from the viewpoints of background and clinical parameters.

Effect of kampo medicine on pain and range of motion of osteoarthritis of the hip accompanied by acetabular dysplasia: case report and literature review.

We report a 52-year-old female with end-stage osteoarthritis of the hip accompanied by acetabular dysplasia in whom quality of life (QOL) was improved by Kampo treatment.When she was 42 years old, she developed pain in the left hip joint, and early-stage OA of the hip was diagnosed by hip joint x-ray. Therefore, she took NSAIDs, and received conservative therapies such as diet and muscle training. However, pain in the hip joint increased and her activity of daily life (ADL) decreased at the age of 50, although she continued to receive the conservative therapies. At the age of 52, she consulted our department requesting Japanese Oriental (Kampo) Medicine. Kampo formulae; Keishikaryojutsubuto (12Tab/day: Kuracie Co. Ltd. Japan), and Boiougito (7.5 g/day: Kuracie Co. Ltd. Japan), were administered. Treatment for 3 months resulted in a decrease in the left hip joint pain using visual analogue scale (VAS) and improvement of her ADL. One year later, her joint symptoms have not increased, and both the Harris hip score and the clinical evaluation criteria of osteoarthritis of the hip have improved.The course of this disease varies depending on the lifestyle of the patient, and Kampo formulations may offer safe, potent supplemental treatment.

A Proteomic Approach for the Diagnosis of 'Oketsu' (blood stasis), a Pathophysiologic Concept of Japanese Traditional (Kampo) Medicine.

'Oketsu' is a pathophysiologic concept in Japanese traditional (Kampo) medicine, primarily denoting blood stasis/stagnant syndrome. Here we have explored plasma protein biomarkers and/or diagnostic algorithms for 'Oketsu'. Sixteen rheumatoid arthritis (RA) patients were treated with keishibukuryogan (KBG), a representative Kampo medicine for improving 'Oketsu'. Plasma samples were diagnosed as either having an 'Oketsu' (n = 19) or 'non-Oketsu' (n = 29) state according to Terasawa's 'Oketsu' scoring system. Protein profiles were obtained by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and hierarchical clustering and decision tree analyses were performed. KBG treatment for 4 or 12 weeks decreased the 'Oketsu' scores significantly. SELDI protein profiles gave 266 protein peaks, whose expression was significantly different between the 'Oketsu' and 'non-Oketsu' states. Hierarchical clustering gave three major clusters (I, II, III). The majority (68.4%) of 'Oketsu' samples were clustered into one cluster as the principal component of cluster I. The remaining 'Oketsu' profiles constituted a minor component of cluster II and were all derived from patients cured of the 'Oketsu' state at 12 weeks. Construction of the decision tree addressed the possibility of developing a diagnostic algorithm for 'Oketsu'. A reduction in measurement/pre-processing conditions (from 55 to 16) gave a similar outcome in the clustering and decision tree analyses. The present study suggests that the pathophysiologic concept of Kampo medicine 'Oketsu' has a physical basis in terms of the profile of blood proteins. It may be possible to establish a set of objective criteria for diagnosing 'Oketsu' using a combination of proteomic and bioinformatics-based classification methods.

Identification of a predictive biomarker for the beneficial effect of a Kampo (Japanese traditional) medicine keishibukuryogan in rheumatoid arthritis patients.

OBJECTIVES: Kampo (Japanese traditional herbal) medicines are now ethically used in Japan as pharmaceutical grade prescription drugs. However, there are distinct groups of responders and non-responders to Kampo medicines. We searched for biomarker candidates to discriminate responders from non-responders to keishibukuryogan (KBG); one of the most frequently used Kampo medicines. DESIGN AND METHODS: A combination of SELDI technology and a decision tree analysis with proprietary developed bioinformatics tools was applied to 41 (32 for tree construction and 9 for validation test) plasma samples obtained from rheumatoid arthritis (RA) patients. A candidate biomarker protein was identified using LC-MS/MS. RESULTS: The constructed tree with measurable reliability contained only a single peak which was identified as haptoglobin alpha 1 chain (Hpalpha1). CONCLUSION: Hpalpha1 is a biomarker candidate for discriminating responders from non-responders to KBG treatment for RA. The present results may open the way to the establishment of "evidence-based" complementary and alternative medicine.

Insights to clinical use of serial determination in titers of cyclic citrullinated peptide autoantibodies.

Anti-cyclic citrullinated peptide (CCP) antibody is a useful marker for the diagnosis and prognosis of rheumatoid arthritis (RA). Recently, clinical significance of follow-up in anti-CCP antibody titer has been pointed out. Thus, we investigated the serial determination in anti-CCP antibodies titer in RA patients. Six patients with RA, who were followed up for longer than 5 years, were assessed in anti-CCP antibodies and radiographs (Larsen score). Anti-CCP antibodies in frozen sera were measured using ELISA. As a result, 6 patients with RA were divided into two groups: one possessed high titers without variation, and the other was without high titers. Joint damage progressed during observation in 2 out of 3 patients with high anti-CCP titers in a retrospective assessment. In contrast, the RA patient, whose anti-CCP titer decreases although it had been high titer at baseline, did not show increase in the Larsen score. These findings suggest that it might be necessary to analyze changes in anti-CCP to predict the prognosis of joint destruction.

No correlation exists between disease activity and the expression of killer-cell immunoglobulin-like receptors in patients with rheumatoid arthritis.

OBJECTIVE: The genes for killer-cell immunoglobulin-like receptors (KIRs) have been cloned and their functions and expression in patients with rheumatoid arthritis (RA) have been partially clarified. However, the correlation between their expression and disease activity has not been analyzed in patients with RA. Thus, we measured KIR expression on lymphocytes in patients with RA, and assessed the correlation between KIR expression and disease activity. PATIENTS AND METHODS: In the cross-sectional study, 15 patients (9 females and 6 males) who fulfilled the diagnostic criteria for RA were assessed. In the longitudinal study, patients who were followed-up for 3 months were assessed. CD158a/b expression on peripheral blood mononuclear cells (PBMC) of RA patients was analyzed using flow cytometry. RESULTS: No significant correlation between KIR expression and CRP, ESR, or IgM-RF was observed. There was no remarkable change in the expression of KIRs between the baseline and after 3 months. Additionally, in the 5 patients whose expression of KIRs particularly changed, the time-related changes in the expression of KIRs were independent from those of inflammation parameters and IgM-RF. CONCLUSION: There was no correlation between KIR expression and disease activity; therefore, the clinical use of KIR expression should be limited, while unnatural KIR expression may be involved in the pathogenesis of RA, but not a recruitment of chronic inflammation to induce joint damage.

Population of CD40L-expressing cells was slightly but not significantly decreased in lymphoid tissues of collagen-induced arthritic mice treated with Hochu-Ekki-To.

OBJECTIVE: To clarify the mechanism of the action of Hochu-Ekki-To (HET) on collagen-induced arthritic (CIA) mice by analyzing the CD40L-expressing cells population. METHODS: CIA was induced in male DBA/1J mice by immunization with two injections of bovine type II collagen (CII). HET or water was orally administered. The subpopulations of lymphocytes obtained from lymph nodes and spleen were detected at 3 weeks after boost using flow cytometry. RESULTS: Although the population of CD4+CD40L+ cells tended to be decreased in the HET group compared to that in control mice, there was no significant difference between the two groups. These findings were observed in lymphocytes obtained from both lymph nodes and spleen. CONCLUSION: HET suppresses the development of CIA. These effects may be partially induced via the decrease in the population of CD4+CD40L+ cells, but the role of this action is probably limited.

Infectious myositis involving the piriformis in a patient with rheumatoid arthritis.

A 49-year-old Japanese woman treated with oral corticosteroids, methotrexate, and infliximab for malignant rheumatoid arthritis was admitted because of fever and low back pain. The white blood cell count and C-reactive protein concentration were elevated. Lumbar and pelvic computed tomography showed enlargement of the piriformis muscle including a hypodense area consistent with gas formation. The patient was treated successfully for infectious myositis with intravenous antibiotics.

Suppressive effect of hochu-ekki-to on collagen induced arthritis in DBA1J mice.

OBJECTIVE: To investigate the effect of hochu-ekki-to (HET) decoction on the development of collagen-induced arthritis (CIA) in mice. METHODS: CIA was induced in male DBA/IJ mice by immunization with 2 injections of bovine type II collagen (CII). HET was orally administered at different doses and with different schedules. The incidence of arthritis, arthritis index, levels of anti-CII antibody, interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) and lymphocyte subsets were examined. RESULTS: HET caused suppression of CIA development in a dose dependent fashion and exerted a suppressive effect on CIA when administered from the first CII immunization or from the onset of CIA, but not when administered for 2 weeks before CII immunization. HET inhibited the production of specific anti-CII antibody, IL-6, and TNF-alpha, and tended to normalize the proportions of cells in lymphocyte subsets. CONCLUSION: HET suppresses the development of CIA, and HET redistributes the population of lymphocytes in lymph node and blood and inhibits IL-6 and TNF-alpha secretion in CIA mice.

[Seven cases of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome].

Among the elderly patients with seronegative polyarthritis, McCarty et al. (1985) proposed a disease entity of "remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome", but only a few cases have been reported in Japan. Here we report 7 cases suspicious of RS3PE syndrome, 2 men and 5 women with an average age of 75.9 years, ranging from 67-82 years. Their common findings were (1) relatively acute onset, (2) polyarthritis, (3) pitting edema of the dorsum of both hands and both feet, and (4) negative rheumatoid factor and antinuclear antibody. McCarty et al. found that RS3 PE syndrome was more prevalent in men; however, in our experience, the opposite was observed. The clinical courses of all patients were good, and they were effectively treated either by small dosages of oral prednisolone, nonsteroidal antiinflammatory drugs, or Chinese herbal (Kampo) medicines. Since this syndrome might not be rare in Japan, it seems necessary to evaluate elderly patients with seronegative polyarthritis with pitting edema as RS3PE syndrome in their routine medical examinations.