K. Inui

Local Application of Basic Fibroblast Growth Factor Minipellet Induces the Healing of Segmental Bony Defects in Rabbits

Abstract. Fibroblast growth factor (FGF) has been reported to increase the volume of callus in a fracture model of rats. There are, however, no reports of successful repair of segmental bony defects by application of an FGF solution. In this study, the effects of basic FGF on the repair of segmental bony defects in the rabbit femur were examined. Minipellet, a new drug delivery system using atelocollagen, was employed to ensure effective delivery of FGF. Segmental bony defects (10 mm in length) were created in the right femurs of 19 rabbits. In pilot studies, no defects of this size healed spontaneously within 6 weeks. Bones were stabilized with miniexternal fixators. Minipellets containing basic FGF were implanted between fragments so as to bridge the two fragments. The healing processes were monitored radiographically and studied histologically. In rabbits in which FGF was added to the defect site at doses of 1.4 μg or higher, approximately 90% of the defects were filled with new bone and cartilage within 6 weeks after minipellet implantation. In rabbits receiving placebo minipellets, however, approximately 15% of the defects were filled by callus within 6 weeks. Furthermore, this callus did not change into mature bone. An injection of 2 μg of FGF solution to bony defects had no effect on the repair of segmental bony defects. These findings suggest that FGF plays a role in the production of adequate volumes of callus particularly in the initial stages of fracture healing and that sustained local release enables FGF to be effective at a low dose. In summary, large segmental bony defects healed after insertion of low-dose FGF minipellets. An adequate dose of FGF and an appropriate delivery system are required for successful healing of large bony defects. These findings imply the potential value of FGF minipellets in clinical practice.

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.

Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study

OBJECTIVEnTo evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept (ETN) (25 mg/week) compared with standard-dose ETN (50 mg/week) in RA.nnnMETHODSnIn this prospective, randomized, open-label study, 70 patients were assigned to receive ETN at either 50 or 25 mg/week for 52 weeks. The primary endpoint was the variation in modified total Sharp score (mTSS), and secondary endpoints were variations in disease activity score in 28 joints (DAS-28), modified HAQ and adverse event rate. Values of mTSS were calculated at baseline and after 52 weeks. Non-progression was estimated as ΔmTSS ≤0.5, and the non-progression rate was compared between groups.nnnRESULTSnMean values at baseline were as follows: disease duration 9.2 years; DAS-28 5.45; and annual progression of mTSS 26.1. No significant differences in background were seen between groups. At 52 weeks, the non-progression rate was significantly less in the 25 mg/week group (36.7%) than in the 50 mg/week group (67.7%) (P = 0.041). Mean ΔmTSS was higher at 25 mg/week (1.03) than at 50 mg/week (-0.13). DAS-28 was significantly improved at 4 weeks, and the effect of treatment lasted for 52 weeks in both groups. No differences in adverse event rates were seen between groups.nnnCONCLUSIONnLow-dose ETN is not inferior to standard-dose ETN in terms of effects on clinical manifestations. However, in terms of the radiographic non-progression rate, the effects of low-dose ETN may be inferior to the effects of standard-dose ETN.nnnTRIAL REGISTRATIONnUMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/, UMIN000001798.

Relationships between serum 25-hydroxycalciferol, vitamin D intake and disease activity in patients with rheumatoid arthritis –TOMORROW study

Abstract Objectives. The effect of serum 25-hydroxycalciferol [25(OH)D] on rheumatoid arthritis (RA) activity remains controversial. This study was undertaken with an aim to clarify the relationship between serum 25(OH)D and RA activity, and to determine the effects of dietary vitamin D intake and age on serum 25(OH)D level. Methods. A total of 208 outpatients with RA were matched according to age and sex with 205 individuals without RA (controls) from the TOMORROW study (UMIN000003876). We excluded 27 patients with RA and 19 control subjects who had been prescribed vitamin D medication or were taking vitamin D supplements. Vitamin D intake was assessed in the remaining 181 patients and 186 controls using the brief-type dietary history questionnaire. Serum 25(OH)D levels were measured using a radioimmunoassay. Results. Serum 25(OH)D levels were significantly lower in patients with RA than in the controls (p < 0.001). There was a significant and positive correlation between age and 25(OH)D in the patients (r = 0.283, p < 0.001), as with vitamin D intake and 25(OH)D, even after adjusting for age (r = 0.313, p < 0.001). Disease activity and 25(OH)D did not significantly correlate. Conclusions. Patients with RA were observed to have serum 25(OH)D levels which correlated with vitamin D intake and age but not disease activity.

Specific serum antibodies against membranous proteins of a human immortal chondrocytic cell line (HCS-2/8) in rheumatoid arthritis and their relationship to the natural history of this disease

An immortal human chondrocytic cell line (HCS-2/8) derived from a chondrosarcoma was used as a source of human antigens to find humoral antibodies to cell surface proteins of human chondrocytes in sera from patients with rheumatoid arthritis (RA). Membrane fractions prepared from the cell line were subjected to Western blot analysis using RA and normal sera as probes. RA sera recognized about a dozen bands, but three of these bands, with molecular weights of 105 kDa, 65 kDa, and 47 kDa, were found to be specific for the RA sera (P<0.05). These bands disappeared following V8 protease digestion, indicating that they were proteins. Among patients with 4 years or more of RA disease activity, reactivity against 105-kDa and 68-kDa proteins was relatively high in those whose joints showed a high degree of erosion. We suspect that levels of these two antibodies are suggestive of changes associated with the natural course of RA.

High serum levels of menatetrenone in male patients with ossification of the posterior longitudinal ligament.

Study Design. This work was performed to investigate the role of vitamin K (VK) in the pathogenesis of ossification of posterior longitudinal ligament (OPLL), by analyzing the biochemical markers of the blood samples of OPLL patients and responses of ligament cells derived from OPLL lesion to VK2. Objectives. The pathogenesis of OPLL, classified as a form of diffuse idiopathic skeletal hyperostosis, is still unclear. In this study, we investigated the role of menaquinone (VK2) in patients with OPLL (OPLL patients) and the effects of VK2 on ligament cells isolated from OPLL lesion. Methods. Serum levels of intact osteocalcin, glu-osteocalcin, MK-4, -7 (VK2 variants) and other minerals in spot blood samples were measured in 24 OPLL patients and in 24 age-matched control patients (non-OPLL patients). The cultured cells isolated from an OPLL patient were treated with MK-4. Alkaline phosphatase (Al-p) activity and osteocalcin release were measured after 2 weeks of culture. Results. In the clinical study, the serum MK-4 in male OPLL patients was significantly higher than that in male non-OPLL patients. However, among female patients, the difference was not significant. Although the serum osteocalcin in females was significantly higher than that in males, there was no significant difference between the OPLL and non-OPLL groups. In in vitro study, MK-4 did not increase Al-p activity in the ligament cells isolated from nonossified region of OPLL patient. Osteoblastic activity of the cultured cells was not stimulated by MK-4. Conclusion. From these results and previous reports, we propose the possibility of the impediment in VK2 metabolism in OPLL patients. The results also implicate the gender tendency in OPLL, because the difference of serum level of MK-4 in OPLL patients was significant only in male.

Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study

BACKGROUND & AIMSnThe Mediterranean diet is reportedly effective in suppressing disease activity in rheumatoid arthritis (RA), but the key elements responsible for this effect remain unknown. The presented study therefore aimed to identify such elements.nnnMETHODSnThis study included 208 consecutive patients with RA (RA group) and 205 age- and sex-matched healthy volunteers (controls) from the prospective TOMORROW cohort studyxa0that has been ongoing since 2010 were included in this study. Food and nutrient intake was assessed using the brief self-administered diet history questionnaire (BDHQ), Mediterranean diet scores were calculated based on intake by controls and disease activity was determined from disease activity scores in 28 joints andxa0erythrocyte sedimentation rates (DAS28-ESR).nnnRESULTSnIntake of monounsaturated fatty acids (MUFA) was significantly lower in the RA, than in the control group (Pxa0=xa00.003) and the ratio of consumed monounsaturated to saturated fatty acid (MUFA/SFA) significantly differed within the RA group after being sub-classified according to DAS28-ESR. Moreover, DAS28-ESR significantly correlated with MUFA/SFA intake after age adjustment (Rxa0=xa0-0.228, Pxa0<xa00.01). Logistic regression analysis selected high MUFA intake as an independent predictor of remission in the RA group with borderline boundary significance (odds ratio, 1.97; 95% CI, 0.98-3.98; Pxa0=xa00.057). Changes in DAS28-ESR between 2010 and 2011 significantly correlated with MUFA/SFA intake after age adjustment (Rxa0=xa00.180, Pxa0=xa00.01).nnnCONCLUSIONSnDaily MUFA intake, a component of the Mediterranean diet score, might suppress disease activity in RA patients.

Combination therapy with biologic agents in rheumatic diseases: current and future prospects.

Strategies in rheumatoid arthritis (RA) based on ‘treat to target’ aim to control disease activity, minimize structural damage, and promote longer life. Several disease-modifying antirheumatic drugs (DMARDs) have been shown to be effective including biological DMARDs (bDMARDs). Treatment guidelines and recommendations for RA have also been published. According to those guidelines, conventional synthetic DMARDs (csDMARDs), as monotherapy or combination therapy, should be used in DMARD-naïve patients, irrespective of the addition of glucocorticoids (GCs). Combination therapies with bDMARDs are also essential for conducting treatment strategies for RA, because in every recommendation or guideline for the management of RA, combination therapies of csDMARDs with bDMARDs are recommended for RA patients with moderate or high disease activity after failure of csDMARD treatment. bDMARDs are more efficacious if used concomitantly with methotrexate (MTX) than with MTX monotherapy or bDMARD monotherapy. Thus, retention has been reported to be longer when combined with MTX. The superior efficacy of combination therapy compared with MTX monotherapy or bDMARD monotherapy could be because: (1) it could help to minimize MTX toxicity by reducing the dose of MTX, thus retention rate of the same therapeutic regimen would become high; (2) anti-bDMARD antibodies are observed at lower concentrations when using MTX concomitantly, so less clearance of bDMARDs via less formation of bDMARD and an anti-bDMARD immune complex; (3) of the additive effects of MTX to bDMARD, especially the combination of tumor necrosis factor inhibitors (TNFis) with MTX. Hence, evidence suggests that combination therapy with bDMARDs is more efficacious than monotherapy using a csDMARD or bDMARD, and that MTX is the best drug for this purpose (if MTX is not contraindicated). Finding the most effective drug regimen at the lowest cost will be the aim of RA treatment in the future.

Reducing glucocorticoid dosage improves serum osteocalcin in patients with rheumatoid arthritis—results from the TOMORROW study

SummaryDecreasing the daily dose of glucocorticoids improved bone metabolic marker levels in patients with rheumatoid arthritis. However, changes in disease activity did not influence bone metabolism. Bone metabolism might thus remain uncontrolled even if disease activity is under good control. Decreasing glucocorticoid dosage appears important for improving bone metabolism.IntroductionPatients with rheumatoid arthritis (RA) develop osteoporosis more frequently than healthy individuals. Bone resorption is increased and bone formation is inhibited in patients with RA, and glucocorticoid negatively affects bone metabolism. We aimed to investigate factors influencing bone metabolic markers in patients with RA.MethodsWe started the 10-year prospective cohort Total Management of Risk Factors in Rheumatoid Arthritis Patients to Lower Morbidity and Mortality (TOMORROW) study in 2010. We compared changes in urinary cross-linked N-telopeptide of type I collagen (uNTx) and serum osteocalcin (OC), as markers of bone resorption and formation, respectively, in 202 RA patients and age- and sex-matched volunteers between 2010 and 2011. We also investigated factors influencing ΔuNTx and ΔOC in the RA group using multivariate analysis.ResultsValues of ΔuNTx were significantly lower in patients with RA than in healthy controls (−0.51 vs. 7.41xa0nmolxa0bonexa0collagenxa0equivalentsu2009(BCE)/mmolxa0creatinine (Cr); pu2009=u20090.0013), whereas ΔOC values were significantly higher in RA patients (0.94 vs. 0.37xa0ng/ml; pu2009=u20090.0065). Changes in prednisolone dosage correlated negatively with ΔOC (βu2009=u2009−0.229, pu2009=u20090.001), whereas changes in disease activity score, bisphosphonate therapy, and period of biologics therapy did not correlate significantly with ΔOC. No significant correlation was seen between ΔuNTx and change in prednisolone dosage.ConclusionsDecreased glucocorticoid dosage improved bone metabolic markers in RA, but disease activity, bisphosphonate therapy, and period of biologics therapy did not influence levels of bone metabolic markers. Decreasing glucocorticoid dosage appears important for improving bone metabolic marker profiles in patients with RA.

Delayed wound healing and postoperative surgical site infections in patients with rheumatoid arthritis treated with or without biological disease-modifying antirheumatic drugs

Biological disease-modifying antirheumatic drugs (bDMARDs) have become more popular for treating rheumatoid arthritis (RA). Whether or not bDMARDs increase the postoperative risk of surgical site infection (SSI) has remained controversial. We aimed to clarify the effects of bDMARDs on the outcomes of elective orthopedic surgery. We used multivariate logistic regression analysis to analyze risk factors for SSI and delayed wound healing among 227 patients with RA (mean age, 65.0xa0years; disease duration, 16.9xa0years) after 332 elective orthopedic surgeries. We also attempted to evaluate the effects of individual medications on infection. Rates of bDMARD and conventional synthetic DMARD (csDMARD) administration were 30.4 and 91.0xa0%, respectively. Risk factors for SSI were advanced age (odds ratio [OR], 1.11; Pu2009=u20090.045), prolonged surgery (OR, 1.02; Pu2009=u20090.03), and preoperative white blood cell count >10,000/μL (OR, 3.66; Pu2009=u20090.003). Those for delayed wound healing were advanced age (OR, 1.16; Pu2009=u20090.001), prolonged surgery (OR, 1.02; Pu2009=u20090.007), preoperative white blood cell count >10,000/μL (OR, 4.56; Pu2009=u20090.02), and foot surgery (OR, 6.60; Pu2009=u20090.001). Risk factors for SSI and medications did not significantly differ. No DMARDs were risk factors for any outcome examined. Biological DMARDs were not risk factors for postoperative SSI. Foot surgery was a risk factor for delayed wound healing.