Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance.

OBJECTIVES: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study. METHODS: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses. RESULTS: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection. CONCLUSIONS: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months. STUDY IDENTIFIER: NCT01932372.

Safety and effectiveness of baricitinib for rheumatoid arthritis in Japanese clinical practice: 24-week results of all-case post-marketing surveillance.

OBJECTIVES: To assess the safety and effectiveness of baricitinib treatment for rheumatoid arthritis (RA) in real-world clinical practice. METHODS: This ongoing all-case post-marketing surveillance study (starting September 2017) includes all patients with RA treated with baricitinib in Japan. Safety and effectiveness (disease activity) were assessed for 24 weeks. RESULTS: Safety analyses to February 2021 included 4731 patients (initial baricitinib dose: 4 mg/day, n = 3058; 2 mg/day, n = 1661; other, n = 12); 1059 (22.38%) were ≥75 years and 3362 (71.06%) previously received biologic therapy. The overall observational period was 1863.14 patient-years; 1174 (24.82%) patients discontinued baricitinib before Week 24, mostly for lack of effectiveness (n = 478; 10.10%). Adverse events occurred in 1271 (26.87%) patients [serious: 203 (4.29%); death: 18 (0.38%)]. The incidence of herpes zoster, hepatic function disorder, and serious infection was 3.09%, 2.77%, and 1.90%, respectively. Malignancy occurred in 17 patients (0.36%) and major adverse cardiovascular events in seven patients (0.15%). Among patients with effectiveness data, at least 26.57% (Boolean) achieved remission at Week 24. CONCLUSIONS: This large nationwide surveillance study evaluated the safety and effectiveness of 24 weeks of baricitinib for RA in real-world clinical practice. Continued surveillance of long-term safety is ongoing.

Comparison of the efficacy and safety of LBAL, a candidate adalimumab biosimilar, and adalimumab reference product in patients with active rheumatoid arthritis inadequately responding to methotrexate: a 52-week phase III randomised study.

OBJECTIVES: To evaluate the similarities between LBAL (adalimumab biosimilar candidate) and the adalimumab reference product (ADL) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 56-week study was conducted in Japan and Korea. During the first 24 weeks, patients subcutaneously received 40 mg of LBAL or ADL every two weeks (LBAL and ADL groups). During the subsequent 28 weeks, the LBAL group patients and half of the ADL group patients received LBAL (L-L and A-L arms). The remaining ADL group patients continued to receive ADL (A-A arm). The primary efficacy endpoint was the change from baseline in disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) at Week 24. American College of Rheumatology (ACR) response rates, adverse events (AEs), and anti-drug antibody (ADA) were also assessed. RESULTS: In total, 383 patients were randomised. The least squares (LS) mean changes from baseline in DAS28-ESR at Week 24 were -2.45 and -2.53 in the LBAL (n=191) and ADL (n=190) groups, respectively. The 95% confidence interval (CI; -0.139, 0.304) of the difference (0.08) was within the pre-specified equivalence margin (-0.6, 0.6). Up to Week 52, the decreases in DAS28-ESR were maintained in all three arms. No notable differences in ACR20/50/70 were observed. The AE and ADA incidences were comparable between the arms. CONCLUSIONS: LBAL was equivalent in efficacy and comparable in safety, including immunogenicity, to ADL. Switching from ADL to LBAL did not impact on efficacy and safety.

A nationwide questionnaire survey on the prevalence of ankylosing spondylitis and non-radiographic axial spondyloarthritis in Japan.

OBJECTIVE: This nationwide study aimed to reveal the prevalence of ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-ax SpA), and the positivity rate of human leukocyte antigen (HLA) among such patients in Japan. METHODS: The first survey was conducted in 2221 randomly selected facilities (26.3%) in September 2018, where the patients with AS/nr-ax SpA were taken care of from January to December 2017. We estimated the total number of these patients using response and extraction rates. A second survey was conducted in 117 facilities (49.8%) to assess for HLA-B27 positivity rate and clinical features. RESULTS: The estimated total numbers of the patients with AS and nr-ax SpA were 3200 (95% confidence interval [CI]: 2400-3900) and 800 (530-1100), suggesting that the prevalence values of AS and nr-ax SpA in general population were 2.6/100,000 (0.0026%) and 0.6/100,000 (0.0006%), respectively. Although 55.5% (76/137) of patients with AS were HLA-B27-positive, those whose age of onset was estimated to be over 50 years tended to undergo less HLA-B27 testing. CONCLUSION: This study revealed the lower prevalence of AS/nr-ax SpA in Japan, compared to those in other countries. Further studies are required to reveal the association of HLA-B27 with the clinical features.

Antiallergic Activity of 6-Deoxy-2-O-methyl-6-(N-hexadecanoyl)amino-l-ascorbic Acid.

Allergy is an excessive immune response to a specific antigen. Type I allergies, such as hay fever and food allergies, have increased significantly in recent years and have become a worldwide problem. We previously reported that an ascorbic acid derivative having palmitoyl and glucosyl groups, 2-O-α-d-glucopyranosyl-6-O-hexadecanoyl-l-ascorbic acid (6-sPalm-AA-2G), showed inhibitory effects on degranulation in vitro and on the passive cutaneous anaphylaxis (PCA) reaction in mice. In this study, several palmitoyl derivatives of ascorbic acid were synthesized and a structure-activity relationship study was performed to discover more potent ascorbic acid derivatives with degranulation inhibitory activity. 6-Deoxy-2-O-methyl-6-(N-hexadecanoyl)amino-l-ascorbic acid (2-Me-6-N-Palm-AA), in which a methyl group was introduced into the hydroxyl group at the C-2 position of ascorbic acid and in which the hydroxyl group at the C-6 position was substituted with an N-palmitoyl group, exhibited much higher inhibitory activity for degranulation in vitro than did 6-sPalm-AA-2G. 2-Me-6-N-Palm-AA strongly inhibit the PCA reaction in mice at lower doses than those of 6-sPalm-AA-2G. These findings suggest that 2-Me-6-N-Palm-AA may be a promising therapeutic candidate for allergic diseases.

Choice of the most appropriate biological disease-modifying anti-rheumatic drug for injection spacing: results from a multicentre observational study.

OBJECTIVES: To determine which biological disease-modifying anti-rheumatic drug (bDMARD) is most appropriate for spacing in patients with rheumatoid arthritis (RA) who have persistent stable symptoms. METHODS: In patients with sustained low disease activity (LDA) or better for ≥3 months who were treated with bDMARDs, the interval between bDMARD injections was extended 1.5 times, and treatment continuation rates at 104 weeks were calculated for each drug. Patients who discontinued therapy owing to adverse reactions and those who withdrew for reasons unrelated to the drugs were excluded. Whether patients could remain in LDA or better after injection spacing was investigated. The targeted drugs were an anti-tumour necrosis factor (TNF) inhibitor (golimumab [GOL]) and 2 non-TNF inhibitors (tocilizumab [TCZ] and abatacept [ABT]). RESULTS: The spacing evaluation included 57, 93, and 40 patients who received GOL subcutaneous injection (SC), TCZ (SC in 21 and drip intravenous injection [DIV] in 72), and ABT (SC in 12 and DIV in 22), respectively. At 104 weeks, the number of patients who discontinued therapy owing to adverse reactions did not significantly differ among the drugs. At 104 weeks, the treatment continuation rate was 0.71 for TCZ SC, 0.70 for GOL, 0.69 for TCZ DIV, 0.55 for ABT SC, and 0.50 for ABT DIV. The continuation rate for ABT was significantly lower than those for GOL and TCZ. No significant difference in continuation rates was observed between SC and DIV. CONCLUSIONS: When the injection interval was extended, GOL and TCZ were superior to ABT in terms of continuation rate.

Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice.

In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.

A randomized double-blind parallel-group phase III study to compare the efficacy and safety of NI-071 and infliximab reference product in Japanese patients with active rheumatoid arthritis refractory to methotrexate.

Objectives: This study aimed to demonstrate the equivalence of NI-071, an infliximab biosimilar (BS), and the infliximab reference product (RP) for treating Japanese patients with active rheumatoid arthritis (RA) refractory to methotrexate.Methods: In this multicenter two-period phase III study, patients were treated with BS or RP for 30 weeks (Period I) in a randomized double-blind manner and then with BS for the following 24 weeks (Period II). The efficacy and safety of BS and RP were compared.Results: The disease activity score in 28-joint count based on erythrocyte sedimentation rate or C-reactive protein and the American College of Rheumatology 20/50/70-based efficacy profiles of BS were similar to those of RP during Period I (30 weeks) including evaluations at week 14, a critical time point. BS efficacy was maintained throughout the 54-week study period. BS efficacy profile matched the RP profile until week 54 after the drug switch from RP to BS at week 30. The safety profiles of BS and RP were comparable and the long-term safety of BS was confirmed.Conclusion: BS demonstrated equivalent efficacy and safety to RP at treatment weeks 14 and 30, and long-term safety until week 54 in Japanese RA patients.

Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study.

OBJECTIVES: We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). METHODS: This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. RESULTS: Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. CONCLUSION: Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA.

Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate.

OBJECTIVE: To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated. RESULTS: In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95% CI -3.198 to -2.820) in the LBEC0101 group and -2.86 (95% CI -3.051 to -2.667) in the ETN-RP group. The estimated between-group difference was -0.15 and its 95% CI was -0.377 to 0.078, which was within the prespecified equivalence margin of -0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs. CONCLUSION: The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP. TRIAL REGISTRATION NUMBER: NCT02357069.

Anti-Allergic Activity of Monoacylated Ascorbic Acid 2-Glucosides.

2-O-α-d-Glucopyranosyl-l-ascorbic acid (AA-2G) is one of the stable ascorbic acid (AA) derivatives known as provitamin C agents. We have previously synthesized two types of monoacylated derivatives of AA-2G, 6-O-acyl-2-O-α-d-glucopyranosyl-l-ascorbic acids having a straight-acyl chain of varying length from C4 to C18 (6-sAcyl-AA-2G) and a branched-acyl chain of varying length from C6 to C16 (6-bAcyl-AA-2G) in order to improve the bioavailability of AA-2G. In this study, 6-sAcyl-AA-2G and 6-bAcyl-AA-2G per se showed the inhibitory effects on hyaluronidase activity and degranulation. 6-sAcyl-AA-2G exhibited strong inhibitory effects on hyaluronidase activity and degranulation in a concentration-dependent manner, and the inhibitory effects tended to become stronger with increasing length of the acyl chain. 2-O-α-d-Glucopyranosyl-6-O-hexadecanoyl-l-ascorbic acid (6-sPalm-AA-2G), which has a straight C16 acyl chain, was the most potent effective for inhibition of hyaluronidase activity and for inhibition of degranulation among the 6-sAcyl-AA-2G derivatives and the two isomers of 6-sPalm-AA-2G. Furthermore, percutaneous administration of 6-sPalm-AA-2G significantly inhibited IgE-mediated passive cutaneous anaphylaxis reaction in mice. These findings suggest that 6-sPalm-AA-2G will be useful for treatment of allergies.

Effectiveness of golimumab for rheumatoid arthritis in patients with an inadequate response to tocilizumab.

OBJECTIVES: Several biological disease-modifying antirheumatic drugs (bDMARDs) are currently available for the treatment of rheumatoid arthritis (RA). Increasing evidence indicates that second-line bDMARDs are effective for inadequate responders to first-line bDMARDs. However, all previous studies investigated the use of tumor necrosis factor inhibitors (TNFi) as a first-line bDMARD, while investigated the efficacy of second-line bDMARDs after the use of tocilizumab (TCZ), a non-TNFi, as a first-line bDMARD. Thus, we investigated the efficacy of golimumab (GLM) as a second-line bDMARD after treatment with TCZ as a first-line bDMARD. METHODS: The final study population consisted of 26 patients (inadequate responders to TCZ; TCZ group) with moderate or high disease activity (DAS28-ESR ≥3.2) at week 24 of treatment with TCZ as a first-line bDMARD or whose DAS28-ESR score worsened after starting TCZ treatment. These patients could be followed for another 52 weeks or more after the subsequent switch to GLM treatment. For comparison, 19 patients treated with TNFi as a first-line bDMARD and inadequate response to TNFi (TNFi group) were included. RESULTS: The DAS28-ESR score at week 52 after the start of treatment with GLM improved significantly compared with baseline in the TCZ and TNFi groups. However, the TCZ group showed significantly better improvement. Patients in both groups had significantly improved treatment outcomes according to European League Against Rheumatism response criteria, but there was no statistically significant difference among them. The retention rate at week 52 after the start of treatment with GLM was significantly higher in the TCZ group than in the TNFi group (81% vs. 68%, respectively). In addition, no difference was found in the progression of bone destruction determined by the change in van der Heijde modified total Sharp scoring system scores between groups. CONCLUSIONS: GLM was an effective therapeutic option for inadequate responders to TCZ.

Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: interim analysis of a post-marketing surveillance study of 2679 patients in Japan.

OBJECTIVE: To determine the real-world safety and effectiveness of iguratimod (IGU) for rheumatoid arthritis (RA), a 52-week, Japanese, post-marketing surveillance study was conducted. An interim analysis at week 24 was performed. METHODS: This study included all RA patients who received IGU following its introduction to the market. All adverse events (AEs) and adverse drug reactions (ADRs) were collected. Effectiveness was evaluated by the change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) from baseline to week 24. RESULTS: Safety was analyzed in 2679 patients. The overall incidences of AEs, ADRs, and serious ADRs were 38.41, 31.65, and 3.21%, respectively; the most commonly reported serious ADRs were pneumonia/bacterial pneumonia, interstitial lung disease, and Pneumocystis jiroveci pneumonia. Concomitant glucocorticoid use and comorbid conditions associated with respiratory disease were identified as risk factors for serious infections. Pulmonary alveolar hemorrhage and increased international normalized ratio of prothrombin time were observed with concomitant use of IGU and warfarin. The DAS28-CRP decreased from baseline to week 24. CONCLUSION: Although a safety concern was identified with concomitant use of IGU and warfarin, this real-world study showed no other new safety concerns and similar effectiveness to clinical trials. IGU is a new therapeutic option for RA patients.

The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis.

OBJECTIVES: Combination treatment with methotrexate, salazosulfapyridine and bucillamine as an alternative to treatment with TNF-inhibiting biologics in rheumatoid arthritis was investigated. METHODS: Twenty-six facilities allied with the Japan Association of Rheumatologists in Private Practice participated in this study. One hundred and twelve patients enrolled in this study, all of whom were within 3 years of diagnosis with rheumatoid arthritis for whom treatment with one DMARD or a combination of two DMARDs had failed (DAS28 > 3.2). Patients chose their own treatment. The triple DMARDs combination group was comprised of 72 patients; the TNF-inhibiting biologics treatment group was comprised of 40 patients. RESULTS: DAS28 scores for the triple DMARDs combination group and the TNF-inhibiting biologics treatment groups were 4.84 ± 0.96 and 5.23 ± 1.26, and there was no significant difference between the two groups. From the 6th month, average disease activities of both groups were reduced, and there was no difference between the two groups at 12 months (DAS28, 3.39 ± 1.43 and 3.05 ± 1.43, p = 0.39). Furthermore, there was no significant difference in the degree of bone destruction between the two groups at 12 months. CONCLUSIONS: The triple DMARD combination therapy provided a new treatment option for those patients for whom treatment with biologics is difficult.

Remarkable efficacy of tocilizumab for treating rheumatoid arthritis in patients with high platelet counts.

OBJECTIVES: To optimize the efficacy of treatment with tocilizumab for rheumatoid arthritis (RA), we comparatively analyzed the outcome of tocilizumab treatment in patients with normal background changes associated closely with IL-6. PATIENTS AND METHODS: The study involved 87 patients with RA satisfying the diagnostic criteria of the American College of Rheumatology (ACR) and receiving continuous tocilizumab treatment for 24 weeks or longer. The outcome of tocilizumab treatment in these patients was comparatively analyzed in relation to the baseline platelet count (the high platelet count group and the normal group), pretreatment hemoglobin levels (the low group and the normal platelet count group), and speed of bone destruction (the rapid progression group and slow progression group). RESULTS: Treatment with tocilizumab significantly improved the 28-joint disease activity score using the erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI), regardless of baseline platelet count, hemoglobin level, or annual speed of bone destruction (ΔTSS). The margins of improvement in DAS28-ESR and CDAI did not differ depending on baseline hemoglobin level or ΔTSS, but the improvement was significantly greater in the high platelet count group than in the normal platelet count group. CONCLUSIONS: These results suggest that in patients with high platelet count, IL-6 is a more important factor involved in RA pathogenesis and that tocilizumab is suitable as a first-line biologic for the treatment of RA patients with high platelet count.

Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre TOcilizumab in Perioperative Period (TOPP) study.

OBJECTIVE: To evaluate perioperative changes in rheumatoid arthritis (RA) patients treated with tocilizumab. METHODS: We collected RA cases with tocilizumab and orthopaedic surgery from 1999 to 2010. Incidences of postoperative infections, delayed wound healing, and RA symptom flare-ups were extracted from the data for comparison with patients without these postoperative events. We also evaluated the changes in C-reactive protein (CRP) and body temperature in patients without postoperative complications with normal CRP before surgery, i.e., patients without postoperative events in whom the tocilizumab level was maintained, for each duration to discontinuation before surgery. RESULTS: A total of 161 cases (n = 122) were collected. The patients had mean age of 56.9 years, and mean disease duration of 12.8 years at operation. Joint replacement surgery was performed in 89 cases. Three patients had postoperative infections (two superficial and one organ/space surgical-site infection), 20 had delayed wound healing, and 36 had RA symptom flare-ups. Delayed wound healing occurred most commonly in patients who underwent spinal surgery (P = 0.0061, versus patients without delayed wound healing). CRP levels were high when tocilizumab was restarted in patients with RA symptom flare-ups (P = 0.0010, versus patients without RA symptom flare-ups). Increased postoperative CRP was observed in patients without postoperative events when the duration from final tocilizumab infusion to surgery was long. The changes in body temperature showed a similar trend to CRP. CONCLUSIONS: Although it has been demonstrated that infection rates in patients treated with tocilizumab are by no means high, incidence of delayed wound healing was significantly higher in cases with surgical interventions such as foot and spinal surgeries. Many patients treated with tocilizumab remained in a normal range of CRP even during the perioperative period. For prevention of perioperative complications, observation of postoperative conditions and surgical wounds, and subjective symptoms of patients are considered important.

Opinions of Japanese rheumatology physicians regarding clinical practice guidelines.

OBJECTIVE: To examine the views of rheumatology physicians concerning clinical practice guidelines in Japan, and changes to them following the dissemination of new guidelines for rheumatoid arthritis (RA) in 2004. DESIGN: Two cross-sectional questionnaire surveys, the first conducted before publication of new evidence-based RA clinical practice guidelines and the second conducted after implementation. SETTING: Rheumatology-focused practices in Japan. PARTICIPANTS: A random sample of physicians registered with the Japan Rheumatism Foundation who satisfied the registration criteria with regard to experience with RA care. RESULTS: The percentage of guideline users increased from 48 to 60% following publication of the new RA guidelines in 2004 (P < 0.01). The majority agreed that clinical practice guidelines support decision-making in practice, although the proportion of supportive responses decreased slightly in the second survey, from 83 to 77% (P < 0.01) for decision-making, while concern about restricting physician autonomy increased from 18 to 22% (P = 0.01). While only 39% of physicians felt that clinical practice guidelines would contribute to malpractice litigation, the proportion of physicians who were concerned that clinical practice guidelines would be used to bring legal action against providers was larger than that who expected they would defend providers (58 vs 30%, P < 0.001). CONCLUSIONS: Clinical practice guidelines are well accepted among Japanese rheumatology physicians, albeit that the proportion decreased slightly after the introduction of new guidelines. One reason for this may be concern about the use of the guidelines in malpractice litigation. To facilitate implementation, trends in physician support for the guidelines should be closely monitored.

Etanercept response in patients with rheumatoid arthritis after secondary loss of efficacy of infliximab.

This study was carried out to determine the effectiveness of half-dose administration of etanercept in patients with rheumatoid arthritis (RA) who exhibited secondary loss of efficacy of infliximab. Seventeen patients were administered 25 mg of etanercept once weekly for at least 1 year after secondary loss of efficacy of infliximab. The mean duration of treatment with infliximab was 32.5 ± 1.3 months. The patient cohort consisted of 3 males and 14 females, with a mean age of 56.3 ± 11.4 years and mean weight of 57.2 ± 10.9 kg. The mean duration of RA was 16.2 ± 10.9 years. The mean Disease Activity Score 28 was decreased significantly, from 5.8 at the initiation of infliximab therapy to 3.6 at the end of observation. There were no withdrawals due to adverse reactions during the study period, although in 2 subjects the agent was changed to tocilizumab due to lack of effect, one after 18 months and the other after 36 months, and 1 subject withdrew after 18 months for financial reasons. A good response can be expected to a half dose of etanercept in patients with secondary loss of efficacy of infliximab. Reduction of the patient's cost burden also makes this a superior treatment.

Effects of an oral administration of glucosamine-chondroitin-quercetin glucoside on the synovial fluid properties in patients with osteoarthritis and rheumatoid arthritis.

The effects of an orally administered combination of a glucosamine-chondroitin-quercetin glucoside (GCQG) supplement on the synovial fluid properties of patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were investigated from the clinical nutrition view point. In this study, forty-six OA and twenty-two RA patients were administered with the GCQG supplement orally for 3 months. Several parameters of the knee joints were monitored before and after supplementation. The OA patients showed a significant improvement in pain symptoms, daily activities (walking and climbing up and down stairs), and visual analogue scale, and changes in the synovial fluid properties with respect to the protein concentration, molecular size of hyaluronic acid, and chondroitin 6-sulphate concentration were also observed. However, no such effects were observed in the RA patients. These results suggest that the GCQG supplement exerted a special effect on improving the synovial fluid properties in OA patients.

Identification of degranulation inhibitors from rooibos (Aspalathus linearis) tea in rat basophilic leukaemia cells.

Quercetin, luteolin and chrysoeriol were identified from rooibos tea as degranulation inhibitors in rat basophilic leukaemia cells. The degranulation inhibitory activity of chrysoeriol was first discovered in the present study. When quercetin, luteolin and chrysoeriol were mixed in the ratio that occurs in rooibos tea extract, the mixture inhibited antigen- and calcium ionophore-stimulated degranulation to the same degree as that by the whole rooibos tea extract. These findings indicate that these three flavonoids are the key factors underlying the degranulation inhibitory activity of rooibos tea.