Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts.

OBJECTIVE: Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for RA via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition. METHODS: CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen-induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment. RESULTS: CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes. CONCLUSION: The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Because the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects.

Effectiveness and safety of treat-to-target strategy in elderly-onset rheumatoid arthritis: a 3-year prospective observational study.

OBJECTIVES: To evaluate 3-year outcomes of following a treat-to-target (T2T) strategy targeting low disease activity for patients with elderly-onset RA (EORA) and to confirm safety profile of T2T. METHODS: Treatment was adjusted to target low disease activity with conventional synthetic DMARDs, followed by biologic DMARDs (bDMARDs) in 197 MTX-naïve EORA patients (mean age 74.9 years) with moderate-to-high disease activity. Non-implementation of T2T was evaluated at week 12, 24, 36, 52, 76, 104 and 128. To evaluate risks of using MTX, bDMARDs and glucocorticoids, 2122 periods of 3 months each were analysed using Bayesian hierarchical logistic regression models. RESULTS: Of the patients, 84.7% received methotrexate, 34.0% glucocorticoids with DMARDs and 41.6% bDMARDs during the observation period. Sixty-nine of the 197 patients failed to adhere to T2T because of comorbidities or the patient's own decision: 33 failed once, 19 twice, 10 three times and 6 four times or more. Simplified disease activity index (SDAI) remission and HAQ Disability Index (HAQ-DI) ≤0.5 at 3 years were achieved in 57.8% and 70.3% of the 128 patients adhering to T2T, and 34.8% and 43.5% of the 69 patients who did not adhere to T2T, respectively, and these were significantly different. Eighty-nine serious adverse events (SAEs) of any type were reported in 61 patients. MTX, bDMARDs and glucocorticoid were not associated with SAEs when adjusted for mean SDAI during the observation period and comorbidities at baseline. CONCLUSION: T2T strategy for EORA by using MTX and bDMARDs was effective with an acceptable safety profile. Adhering to T2T led to better outcomes.

Radiographic and clinical effects of 10 mg and 25 mg twice-weekly etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis.

OBJECTIVES: To compare the radiographic and clinical effects of 25 versus 10 mg twice-weekly (BIW) etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis (RA). METHODS: This was a post-hoc analysis of a Phase 3 study where Japanese patients with active RA were randomized to receive BIW etanercept 25 mg (n = 182), etanercept 10 mg (n = 192), or methotrexate (n = 176) for 52 weeks (NCT00445770). This analysis included assessments of week-24 and week-52 disease activity, week-52 radiographic progression, and the relationship between baseline characteristics and week 52 clinical outcomes with clinically relevant radiographic progression (CRRP) at week 52. RESULTS: At week 52, there were no significant differences between 25 and 10 mg etanercept in terms of achieving low disease activity or remission. CRRP was observed in 36% and 32% of patients in the 10 and 25 mg groups, respectively. Predictor analysis suggested that worse background disease status, treatment with methotrexate rather than etanercept, and poorer clinical outcomes at week 52 were associated with CRRP. CONCLUSIONS: The 25 mg BIW etanercept dosage does not appear to be significantly more efficacious than 10 mg in Japanese patients with RA. Further studies evaluating the optimal etanercept dosing regimen in this patient population may be merited. NCT: NCT00445770.

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis - A systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach. METHODS: We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations. RESULTS: We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day. CONCLUSION: Tacrolimus is effective with acceptable safety in the management of RA.

Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial.

OBJECTIVES: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. METHODS: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. RESULTS: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. CONCLUSION: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis/dermatomyositis: a single-arm clinical trial.

OBJECTIVE: Interstitial pneumonia is common and has high short-term mortality in patients with PM and DM despite glucocorticoid (GC) treatment. Retrospective studies suggested that the early use of immunosuppressive drugs with GCs might improve its short-term mortality. METHODS: A multicentre, single-arm, 52-week-long clinical trial was performed to test whether the initial combination treatment with tacrolimus (0.075 mg/kg/day, adjusted for the target whole-blood trough levels between 5 and 10 ng/ml) and GCs (0.6-1.0 mg/kg/day of prednisolone followed by a slow taper) improves short-term mortality of PM/DM-interstitial pneumonia patients. The primary outcome was overall survival. We originally intended to compare, by using propensity-score matching, the outcome data of clinical trial patients with that of historical control patients who were initially treated with GCs alone. RESULTS: The 52-week survival rate with the combination treatment (N = 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose GCs individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients. CONCLUSION: Our study provided findings which suggest that initial treatment with tacrolimus and GCs may improve short-term mortality of PM/DM-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00504348.

Radiographic and clinical outcomes following etanercept monotherapy in Japanese methotrexate-naïve patients with active rheumatoid arthritis.

Objectives: Compare outcomes with methotrexate (MTX) or etanercept (ETN) monotherapy in Japanese patients with active rheumatoid arthritis (RA) who were MTX-naïve or with intolerance or inadequate response to prior MTX (MTX-IR).Methods: Post hoc analysis of a phase 3 study comparing MTX, ETN 10 mg twice weekly, and ETN 25 mg twice weekly in Japanese patients with RA. Disease activity was evaluated using American College of Rheumatology (ACR) scores and 28-joint Disease Activity Score (DAS28), radiographic progression evaluated using van der Heijde's modified Total Sharp Score (mTSS), and functional status evaluated using Health Assessment Questionnaire Disability Index (HAQ-DI).Results: Among MTX-naïve and MTX-IR patients, greater proportions of those randomized to either ETN group achieved ACR20, ACR50, ACR70, DAS28 ≤3.2 or <2.6, clinically relevant inhibition of mTSS changes, and reductions in HAQ-DI compared with MTX at the majority of time points. There were very few clinically meaningful differences between ETN groups for any of the variables evaluated.Conclusion: ETN monotherapy was more effective than MTX in both MTX-naïve and MTX-IR patients, with very few clinically meaningful differences between ETN 10 mg and ETN 25 mg when given twice weekly. The relative benefits of ETN were greater in MTX-naïve patients than MTX-IR patients.ClinicalTrials.gov identifierNCT00445770.

Epidemiological characteristics of rheumatoid arthritis in Japan: Prevalence estimates using a nationwide population-based questionnaire survey.

Objectives: To elucidate the epidemiological characteristics of patients with rheumatoid arthritis (RA) in Japan using data from the Comprehensive Survey of Living Conditions, a nationwide questionnaire survey conducted in 2016.Methods: In total, 222,365 men and 245,251 women aged ≥16 years were included in the study. RA patients were defined as those who reported 'currently receiving treatment for RA at hospitals, clinics, or a facility for Japanese traditional massage, acupuncture, moxibustion, or judo-orthopedics.' The number of RA patients was estimated from the age-specific prevalence and total Japanese population in 2016. Further, the prevalence of individuals experiencing difficulties in activities of daily living due to health problems and those with mental distress as evaluated by K6 Scale was examined.Results: The estimated number and prevalence of RA in Japan with 95% confidence interval was 822 (768-880) thousand and 0.75% (0.70-0.80%). The population peaked in the late 60s, and the prevalence continued increasing until the early 80s, regardless of sex. Compared with non-RA participants, RA patients were more likely to experience difficulties in activities and to be distressed.Conclusion: High prevalence of RA in older age and mental and physical burden among RA patients were confirmed.

Predictive value of serum amyloid a levels for requirement of concomitant methotrexate in tocilizumab initiation: A post hoc analysis of the SURPRISE study.

Objectives: To identify predictive factors for remission by tocilizumab monotherapy in rheumatoid arthritis (RA) patients.Methods: This is a post hoc analysis of the SURPRISE study, a 2-year randomized, controlled study comparing the efficacy of tocilizumab with (ADD-ON) and without methotrexate (SWITCH). The primary endpoint was DAS28-ESR remission (<2.6) at week 24. The change in modified total Sharp score from baseline to week 52 (ΔmTSS/year) was also assessed as an endpoint. The effect of clinical parameters at baseline on remission was estimated by logistic regression analysis.Results: In SWITCH (n = 96), CRP, SAA, RF, and DAS28 at baseline showed predictive value for DAS28 remission in unadjusted analysis. Adjusted analysis confirmed SAA and DAS28 as predictive factors, with SAA having the highest value (ROC-AUC = 0.731). Furthermore, structural remission (ΔmTSS/year ≤ 0.5) rate was significantly higher in patients with SAA of < 50.0 µg/mL than other patients. In contrast, in ADD-ON (n = 98), only DAS28 showed predictive value for DAS28 remission. In patients with SAA < 50.0 µg/mL, both DAS28 remission and structural remission rate were comparable between SWITCH and ADD-ON.Conclusion: RA patients with low SAA levels at baseline may benefit similarly from tocilizumab with and without methotrexate.Trial registration number: NCT01120366.

Higher risk of hospitalized infection, cardiovascular disease, and fracture in patients with rheumatoid arthritis determined using the Japanese health insurance database.

Objective: To evaluate the risk of hospitalized infection (HI), cardiovascular disease (CVD), stroke, and fracture in rheumatoid arthritis (RA) patients compared with non-RA patients using the Japanese health insurance database. Method: Among individuals aged ≥18 years, RA cases were defined to have one RA diagnostic code and receiving ≥1 disease-modifying antirheumatic drug between 2005 and 2013 (n = 6,712). Age-, sex-, calendar year of the observation start-, and observation length-matched non-RA cases were selected at 1:5 (n = 33,560). Hazard ratios (HRs) were calculated using the time-dependent Cox regression analysis. Results: Median age of the patients was 52.0 years. The incidence rates of HI, CVD, and fracture in the RA group were 2.42/100 person-years (PY), 4.94/1,000 PY, and 10.59/1,000 PY. The crude incidence rate ratios (95% CI) (RA vs. non-RA) for HI, CVD, and fracture were 2.47 (2.20-2.77), 1.89 (1.49-2.41), and 3.35 (2.80-4.02). The adjusted HR (95% CI) (RA vs. non-RA) was significantly elevated (HI, 1.74 [1.52-1.99], CVD, 1.38 [1.04-1.85], and fracture, 1.88 (1.54-2.31)]. Conclusion: The relatively young RA population had significantly higher risks of these complications than the non-RA, indicating importance of prevention of them even at young ages in clinical settings.

Three-year safety and two-year effectiveness of etanercept in patients with rheumatoid arthritis in Japan: Results of long-term postmarketing surveillance.

Objectives: To evaluate the real-world safety and effectiveness of etanercept (ETN) in Japanese patients with rheumatoid arthritis. Methods: This postmarketing surveillance study (NCT00503139) assessed the safety and effectiveness of ETN treatment over 3 and 2 years (from June 2007 to September 2011), respectively. Safety was evaluated by occurrence and seriousness of adverse drug reactions (ADRs), and of adverse events (AEs) for malignancies. Effectiveness was assessed using the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (ESR) with four variables (swollen and tender joint counts, ESR, and patient global assessment; DAS28-4/ESR). Treatment was considered effective if patients had a good/moderate response by the European League Against Rheumatism response criteria. Results: ADRs occurred in 256/675 (37.9%) patients, the most common being injection site reactions (4.4%) and nasopharyngitis (3.3%). Serious ADRs occurred in 60/675 (8.9%) patients, the most frequent being pneumonia (1.2%). The incident rate of malignancies (AEs) was 1.06 per 100 patient-years. Mean baseline DAS28-4/ESR for the 581 patients included in effectiveness analysis was 5.42, which decreased to 3.32 at 2 years. Eighty-two percent of patients achieved a moderate/good response at 2 years. Conclusion: Long-term ETN treatment safety and effectiveness were sustained over 3 and 2 years, respectively.

Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomised controlled study (the second year of the SURPRISE study).

OBJECTIVE: To evaluate the sustained remission and low disease activity after discontinuation of tocilizumab in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate. METHODS: The SURPRISE study was a 2-year, open-label randomised controlled study. Among patients who had been randomised to additional tocilizumab (ADD-ON) or switch to tocilizumab (SWITCH) in the first year, those who achieved remission based on the disease activity score for 28 joints (DAS28-ESR<2.6) discontinued tocilizumab at week 52 and were observed for the following 52 weeks. The endpoint of the second year included tocilizumab-free remission and low disease-activity rates, functional outcome, radiological outcomes assessed with the modified total Sharp score (mTSS) and safety. The efficacy of reinstituted tocilizumab/methotrexate was also evaluated. RESULTS: A total of 105 patients who achieved remission at week 52 discontinued tocilizumab; 51 in ADD-ON continued methotrexate and 54 in SWITCH received no disease-modifying antirheumatic drugs. Sustained DAS28 low disease-activity rates were significantly higher in ADD-ON than in SWITCH (55%vs27%, p=0.005). Sustained remission rates at week 104 were 24% for ADD-ON and 14% for SWITCH (p=0.29). Radiological progression was comparable between both groups (mTSS; 0.37vs0.64, p=0.36). The restart of tocilizumab induced remission in all except two patients after 36 weeks, irrespective of concomitant methotrexate. CONCLUSION: Sustained low disease activity after tocilizumab discontinuation could be maintained with continued methotrexate in more than half of the patients. Retreatment with tocilizumab led to remission in more than 90% of patients. TRIAL REGISTRATION NUMBER: NCT01120366; Results.

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120.

OBJECTIVE: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. METHODS: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. RESULTS: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. CONCLUSION: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial.

OBJECTIVES: To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone. METHODS: MTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX→MTX; n=108, PBO+MTX→MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP. RESULTS: 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups. CONCLUSIONS: In MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years, even after stopping CZP. TRIAL REGISTRATION NUMBER: NCT01451203.

A sphingosine 1-phosphate receptor agonist ameliorates animal model of vasculitis.

OBJECTIVES: Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to cell surface receptors (S1P1-5). In this study, we examined the effect of S1P1 agonist, ONO-W061, on murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis. METHODS: Mice were administered ONO-W061, and the number of peripheral blood cells was counted. Vasculitis was induced by an intraperitoneal injection of CAWS. Expression of S1P receptors and CXCL1 was analyzed by quantitative RT-PCR. ONO-W061 was orally administered, and vasculitis was evaluated histologically. Number of neutrophils, macrophages and T cells in the vasculitis tissue was counted using flow cytometry. Production of chemokines from S1P-stimulated human umbilical vein endothelial cells (HUVECs) was measured by ELISA. RESULTS: Number of peripheral blood lymphocytes was decreased by ONO-W061. Expression of CXCL1 and S1P1 was enhanced in CAWS-induced vasculitis tissue. Vasculitis score, CXCL1 and number of neutrophils in the vasculitis tissue were lower in ONO-W061-treated mice. Treatment of HUVECs with S1P upregulated the production of CXCL1 and IL-8 in vitro, and this was inhibited by ONO-W061. CONCLUSIONS: ONO-W061 significantly improved CAWS-induced vasculitis. This effect may be partly exerted through the inhibited production of chemokines by endothelial cells, which in turn could induce neutrophil recruitment into inflamed vessels.

Direct suppression of autoaggressive CD8+ T cells with CD80/86 blockade in CD8+ T cell-mediated polymyositis models of mice.

OBJECTIVES: CD80/86 blockade to inhibit CD28 costimulation suppressed alloreactive human and murine CD4+ T cells but not alloreactive CD8+ T cells. In contrast, CD28 costimulation augments CD8+ T cell-mediated cell lysis in antigen-nonspecific stimulation. The present study was conducted to discern whether the CD80/86 blockade exerts therapeutic effects on CD8+ T cell-mediated polymyositis (PM) models of mice and whether the effects could be attributable to direct suppression of autoantigen-specific CD8+ T cells. METHODS: C protein-induced myositis (CIM) was induced in mice with intradermal injection of C protein fragments. C protein peptide-induced myositis (CPIM), in which autoaggressive CD8+ T cells are activated without CD4+ T cell help, was induced in mice with intravenous injection of dendritic cells (DCs) loaded with CD8+ T cell-epitope peptides derived from the C protein fragment. The immunised mice were treated with CTLA4-Ig or anti-CD80 and anti-CD86 antibodies (anti-CD80/86 Abs). The muscles were evaluated histologically 21 days after the C protein immunisation or 7 days after the DC injection. RESULTS: CIM was suppressed in the mice treated with CTLA4-Ig or anti-CD80/86 Abs administered prophylactically from the day of immunisation and therapeutically after the disease onset. CPIM was suppressed when CTLA4-Ig was administered concurrently with the DC injection. CONCLUSIONS: The CD80/86 blockade was effective in PM models of mice. Amelioration of CPIM indicates direct suppression of CD8+ T cells by the CD80/86 blockade. CTLA4-Ig should be a potential therapeutic agent of PM and other CD8+T cell-mediated diseases by suppressing both autoantigen-specific CD4+ and CD8+ T cells.

Temporal expression of growth factors triggered by epiregulin regulates inflammation development.

In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases.

Integrating patients' perceptions into clinical practice guidelines for the management of rheumatoid arthritis in Japan.

OBJECTIVE: Patients' values and preferences are among the key factors that determine the strength of recommendations presented in clinical practice guidelines (CPG). The aim of this study was to summarize the integration process for patients' perceptions into the development of CPG for rheumatoid arthritis (RA) management in Japan. METHODS: We used a mixed-methods approach. Questionnaires that could be self-administered were mailed to 2222 RA patients randomly selected from the Japan Rheumatism Friendship Association (JRFA) membership list that was age- and prefecture-stratified. A focus group with five JRFA executive members was formed to verify the results of the questionnaire. RESULTS: A total of 1470 patients aged 20-79 years old returned the questionnaire. Analysis of the questionnaire data revealed that the topics selected by the CPG task force met the patients' needs. The focus group participants showed reluctance to use the term 'preference' because patients would not want to take any medications but would have to take them out of necessity. CONCLUSIONS: We confirmed that the new CPG successfully addressed clinical issues that were important to both rheumatologists and patients. Clinicians should understand patients' reluctance to take medications and explain the role of each medication well to increase adherence.

Simplified Disease Activity Index remission at month 6 is an independent predictor of functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis: A multi-center, prospective cohort study in Japan.

OBJECTIVE: To evaluate association of clinical remission at month 6 with functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis (RA). METHODS: This 12-month prospective, multicenter cohort study enrolled 168 patients with RA who started abatacept. Outcomes were assessed using composite measures, quality of life indices, and the van der Heijde-modified total Sharp score (mTSS). The logistic regression analysis was applied to identify factors associated with outcomes and their odds ratios (OR) with 95% confidence interval (95% CI). RESULTS: At month 6 and 12, 21.4% and 26.2% of the patients achieved Simplified Disease Activity Index (SDAI) remission (SDAI <3.3), and 40.6% and 41.7% achieved Health Assessment Questionnaire-Disability Index (HAQ-DI <0.5) remission. Among 129 patients whose mTSS progression was evaluated at month 12, 83 (64.3%) achieved structural remission (ΔmTSS ≤0.5 for 12 months). SDAI remission at month 6 was identified as a significant predictor of both functional (OR, 3.732; 95% CI, 1.328-10.489) and structural remissions (OR, 4.301; 95% CI, 1.298-14.243) at month 12 after adjusting for covariates. CONCLUSIONS: Aiming for SDAI remission at month 6 is an appropriate strategy to obtain good functional and structural outcomes at month 12.

Achieving simplified disease activity index remission in patients with active rheumatoid arthritis is associated with subsequent good functional and structural outcomes in a real-world clinical setting under a treat-to-target strategy.

OBJECTIVE: To verify predictive validity of simplified disease activity index (SDAI) remission for subsequent functional and structural outcomes in real-world clinical settings under a treat-to-target strategy (T2T). METHODS: In this multicenter, prospective cohort study, T2T was implemented in rheumatoid arthritis (RA) patients with moderate-to-high disease activity. SDAI or clinical disease activity index (CDAI) was assessed every 12 weeks, and treatment was adjusted to achieve clinical remission or low disease activity (LDA). Multivariate logistic regression models were used to examine the associations of SDAI remission (≤3.3) at week 24 with the health assessment questionnaire-disability index (HAQ-DI) ≤ 0.5 or with the delta van der Heijde-modified total Sharp score (ΔvdH-mTSS)