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ID PMID Title PublicationDate abstract
25090614 Synergistic effects of ethanol and isopentenyl pyrophosphate on expansion of γδ T cells 2014 Low to moderate ethanol consumption has been associated with protective effects in autoimmune diseases such as rheumatoid arthritis, RA. An expansion of γδ T cells induced by isopentenyl pyrophosphate, IPP, likewise seems to have a protective role in arthritis. The aim of this project was to test the hypothesis that low doses of ethanol can enhance IPP-induced expansion of synovial fluid γδ T cells from patients with arthritis and may thereby potentially account for the beneficial effects of ethanol on symptoms of the arthritic process. Thus, mononuclear cells from synovial fluid (SF) from 15 patients with arthritis and from peripheral blood (PB) from 15 healthy donors were stimulated with low concentrations of ethanol and IPP for 7 days in vitro. IPP in combination with ethanol 0.015%, 2.5 mM, equivalent to the decrease per hour in blood ethanol concentration due to metabolism, gave a significantly higher fractional expansion of SF γδ T cells compared with IPP alone after 7 days (ratio 10.1+/-4.0, p<0.0008, n = 12) in patients with arthritis. Similar results were obtained for PB γδ T cells from healthy controls (ratio 2.0+/-0.4, p<0.011, n = 15). The augmented expansion of γδ T cells in SF is explained by a higher proliferation (p = 0.0034, n = 11) and an increased survival (p<0.005, n = 11) in SF cultures stimulated with IPP plus ethanol compared to IPP alone. The synergistic effects of IPP and ethanol indicate a possible allosteric effect of ethanol. Similar effects could be seen when stimulating PB with ethanol in presence of risedronate, which has the ability to increase endogenous levels of IPP. We conclude that expansion of γδ T cells by combinatorial drug effects, possibly in fixed-dose combination, FDC, of ethanol in the presence of IPP might give a protective role in diseases such as arthritis.
24510027 Reliability, validity, and responsiveness of the Persian version of the rheumatoid and art 2015 Jan The aims of this study were to cross-culturally translate the original rheumatoid and arthritis outcome score (RAOS) into Persian and evaluate its reliability, validity, and responsiveness in a group of patients with rheumatoid arthritis (RA). The questionnaire was translated through a standard forward-backward translation. A sample of 103 patients was asked to complete the Persian RAOS, the Short Form-36 (SF-36), and the arthritis impact measurement scale-short form (AIMS2-SF). To determine test-retest reliability, the Persian RAOS was readministered to a sample of 50 patients, 3-6 days after the first visit. To evaluate responsiveness, 50 patients completed the Persian RAOS at baseline and at the end of a pharmacological intervention. Test-retest reliability and internal consistency were assessed using intraclass correlation coefficient (ICC) and Cronbach's alpha, respectively. Construct validity was assessed by comparing the results of the RAOS with the Persian SF-36 and AIMS2-SF using Spearman's correlation coefficient. Responsiveness was assessed by the calculation of effect size (ES) and standardized response means (SRM). The acceptable level of ICC > 0.70 and Cronbach's alpha > 0.70 were obtained for the most RAOS subscales. As expected, moderate to strong correlations were observed between subscales of the RAOS and the SF-36/AIMS2-SF intended to measure similar constructs. The ES range of 0.18 to 0.51 and the SRM range of 0.25 to 0.91 were obtained for the RAOS subscales. In conclusion, the Persian RAOS is a reliable, valid, and responsive outcome measure for patients with RA suffering from arthritis in the lower limb joints.
23238605 Urinary tract infections in patients with rheumatoid arthritis. 2013 Mar Co-morbidity from rheumatoid arthritis (RA) has recently focussed on outcomes of cardiovascular and pulmonary disease, but serious infections are an increasingly well-recognised complication of RA. Recent work has demonstrated how the incidence of pneumonia can be reduced in RA, but little attention has been paid to the incidence of urinary tract infection (UTI) in RA or to the associated co-morbidity. The aim of this study was to describe the incidence of UTI leading to hospitalisation in a large cohort of patients with RA and investigate which factors contributed to this. This study assessed all patients with RA hospitalised over a 12-month period with a discharge diagnosis including UTI. Patients were identified through a PAS records search in a single large centre. Historical case controls without RA matched for age and gender were identified from the literature. Clinical notes were manually examined by two observers. We recorded: age, gender, duration of RA, number of UTI, all RA therapy, co-morbidity, results of urine and blood cultures with antimicrobial sensitivities, readmission rates, treatment and outcome. We calculated the relative risk (RR) of developing UTI in patients with RA and the factors influencing this. From a population of 2,200 RA patients, the overall annual incidence of hospitalisation with UTI amongst RA patients was 2.09 %, as against 0.97 and 0.91 % for two control groups (RR = 2.16 and 2.29). Most patients (90 %) were female, and the group mean age was 76 years. The use of long-term oral steroids as sole therapy was associated with a RR of 6.8 for UTI (p = 0.002) while failure to take disease-modifying anti-rheumatic drugs (DMARDs) was associated with a similar RR of 6.7 (p = 0.001). Positive cultures for Escherichia coli were found in 51 % of RA patients. Relevant co-morbidities included permanent catheters, vaginal prolapse, cancer and diabetes. Recurrence of UTI within a year was common. RA was associated with a higher-than-expected incidence of UTI, particularly among older females. This was associated with the use of long-term oral steroids and the absence of DMARDs. Other factors included female gender, greater age and long disease duration. We recommend avoidance of long-term oral steroids but consideration of low-dose prophylactic antibiotics in those patients with recurrent UTI.
24369907 Collagenase-3 (MMP-13) deficiency protects C57BL/6 mice from antibody-induced arthritis. 2013 INTRODUCTION: Matrix metalloproteinases (MMPs) are important in tissue remodelling. Here we investigate the role of collagenase-3 (MMP-13) in antibody-induced arthritis. METHODS: For this study we employed the K/BxN serum-induced arthritis model. Arthritis was induced in C57BL/6 wild type (WT) and MMP-13-deficient (MMP-13–/–) mice by intraperitoneal injection of 200 μl of K/BxN serum. Arthritis was assessed by measuring the ankle swelling. During the course of the experiments, mice were sacrificed every second day for histological examination of the ankle joints. Ankle sections were evaluated histologically for infiltration of inflammatory cells, pannus tissue formation and bone/cartilage destruction. Semi-quantitative PCR was used to determine MMP-13 expression levels in ankle joints of untreated and K/BxN serum-injected mice. RESULTS: This study shows that MMP-13 is a regulator of inflammation. We observed increased expression of MMP-13 in ankle joints of WT mice during K/BxN serum-induced arthritis and both K/BxN serum-treated WT and MMP-13–/– mice developed progressive arthritis with a similar onset. However, MMP-13–/– mice showed significantly reduced disease over the whole arthritic period. Ankle joints of WT mice showed severe joint destruction with extensive inflammation and erosion of cartilage and bone. In contrast, MMP-13–/– mice displayed significantly decreased severity of arthritis (50% to 60%) as analyzed by clinical and histological scoring methods. CONCLUSIONS: MMP-13 deficiency acts to suppress the local inflammatory responses. Therefore, MMP-13 has a role in the pathogenesis of arthritis, suggesting MMP-13 is a potential therapeutic target.
24020712 Is the Arthritis Impact Measurement Scales 2 a good tool to assess quality of life in Slov 2013 OBJECTIVES: The aim of this study is to evaluate the measurement properties of the Arthritis Impact Measurement Scales 2 (AIMS2) in Slovak patients with rheumatoid arthritis (RA). BACKGROUND: RA impacts all aspects of life quality (QoL). Many instruments for QoL in RA patients frequently assess only biological aspects. The AIMS2 instrument covers physical, emotional and social QoL and it is widely and successfully used as an indicator of the outcomes of care for arthritis patients, but not in Slovak RA patients. METHODS: After translation 178 patients with RA were asked to complete the AIMS2, Visual Analogue Scale for pain - VAS, Health Assessment Questionnaire Disability Index - HAQ-DI, Beck Anxiety Inventory - BAI and Zung Self-Rating Depression Scale - SDS to analyse the validity of the Slovak-AIMS2. Pearson correlations, one-way analysis of variance (ANOVA), t-test, and principal component analysis were used to test validity of AIMS2. The reliability was assessed by internal consistency, as estimated by Cronbach's alpha coefficients, and using the test-retest procedure. RESULTS: The Cronbach's alpha coefficients for AIMS2 scales ranged from 0.78 to 0.94, the test-retest reliability was significant (p<0.05), ranging from 0.61 to 0.99. The correlations between most of the Slovak-AIMS2 scales and HAQ-DI, VAS, BAI and SDS were statistically significant (p<0.05). The principal component analysis identified three factor models explaining 66.82 % of the variance. CONCLUSIONS: The results showed that Slovak-AIMS2 is culturally appropriate, valid and reliable for measuring the health status in adult RA patients (Tab. 6, Ref. 20).
25273676 Activation of fibroblast-like synoviocytes derived from rheumatoid arthritis via lysophosp 2014 Oct 2 INTRODUCTION: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to G protein-coupled receptors (LPA1-6). Recently, we reported that abrogation of LPA receptor 1 (LPA1) ameliorated murine collagen-induced arthritis, probably via inhibition of inflammatory cell migration, Th17 differentiation and osteoclastogenesis. In this study, we examined the importance of the LPA-LPA1 axis in cell proliferation, cytokine/chemokine production and lymphocyte transmigration in fibroblast-like synoviocytes (FLSs) obtained from the synovial tissues of rheumatoid arthritis (RA) patients. METHODS: FLSs were prepared from synovial tissues of RA patients. Expression of LPA1-6 was examined by quantitative real-time RT-PCR. Cell surface LPA1 expression was analyzed by flow cytometry. Cell proliferation was analyzed using a cell-counting kit. Production of interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), chemokine (C-C motif) ligand 2 (CCL2), metalloproteinase 3 (MMP-3) and chemokine (C-X-C motif) ligand 12 (CXCL12) was measured by enzyme-linked immunosorbent assay. Pseudoemperipolesis was evaluated using a coculture of RA FLSs and T or B cells. Cell motility was examined by scrape motility assay. Expression of adhesion molecules was determined by flow cytometry. RESULTS: The expression of LPA1 mRNA and cell surface LPA1 was higher in RA FLSs than in FLSs from osteoarthritis tissue. Stimulation with LPA enhanced the proliferation of RA FLSs and the production of IL-6, VEGF, CCL2 and MMP-3 by FLSs, which were suppressed by an LPA1 inhibitor (LA-01). Ki16425, another LPA1 antagonist, also suppressed IL-6 production by LPA-stimulated RA FLSs. However, the production of CXCL12 was not altered by stimulation with LPA. LPA induced the pseudoemperipolesis of T and B cells cocultured with RA FLSs, which was suppressed by LPA1 inhibition. In addition, LPA enhanced the migration of RA FLSs and expression of vascular cell adhesion molecule and intercellular adhesion molecule on RA FLSs, which were also inhibited by an LPA1 antagonist. CONCLUSIONS: Collectively, these results indicate that LPA-LPA1 signaling contributes to the activation of RA FLSs.
23607884 Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis. 2013 Jul Rodent models for arthritis implicate a role for complement in disease development and progression. In humans, complement deposition has been observed in inflamed synovia of rheumatoid arthritis (RA) patients. In this study we analysed whether genetic variants of complement component C1q predispose to RA. We genotyped single nucleotide polymorphisms (SNPs) in and around the C1q genes, C1qA, C1qB and C1qC, in a Dutch set of 845 RA cases and 1046 controls. Replication was sought in a sample set from North America (868 cases/1193 controls), and a meta-analysis was performed in a combined samples set of 8000 cases and 23 262 controls of European descent. We determined C1q serum levels in relation to C1q genotypes. In the discovery phase, five of the 13 SNPs tested in the C1q genes showed a significant association with RA. Additional analysis of the genomic area around the C1q genes revealed that the strongest associating SNPs were confined to the C1q locus. Within the C1q locus we observed no additional signal independent of the strongest associating SNP, rs292001 [odds ratio (OR) = 0·72 (0·58-0·88), P = 0·0006]. The variants of this SNP were associated with different C1q serum levels in healthy controls (P = 0·006). Interestingly, this SNP was also associated significantly in genome-wide association studies (GWAS) from the North American Rheumatoid Arthritis Consortium study, confirming the association with RA [OR = 0·83 (0·69-1·00), P = 0·043]. Combined analysis, including integrated data from six GWAS studies, provides support for the genetic association. Genetic variants in C1q are correlated with C1q levels and may be a risk for the development of RA.
23510877 Left atrial myxoma on FDG-PET/CT. 2013 Nov A 56-year-old woman with rheumatoid factor-positive rheumatoid arthritis underwent FDG-PET/CT because of fatigue, fever, coughing, and weight loss for several months. FDG-PET/CT solely revealed a mildly hypermetabolic hypodense area in the left atrium. Subsequently, transthoracic echocardiography and contrast-enhanced MRI showed a left atrial pedunculated soft tissue mass suggestive for myxoma, with histological confirmation. Myocardial involvement by tumors is rare, and FDG-PET/CT has been very useful for identifying cardiac metastases. However, very few cases have been reported using FDG-PET/CT for detecting primary cardiac tumors, but as shown here, abnormal focal myocardial uptake should trigger further morphological assessment.
23773634 Potential food-drug interactions in patients with rheumatoid arthritis. 2013 Apr Various medications are used for the treatment of rheumatoid arthritis (RA). Food-drug interactions may occur with concomitant ingestion of particular food. For example, methotrexate (MTX), the anchor drug in the therapeutic strategy against RA, is an antifolate agent. Excessive presence or absence of dietary folic acid may regulate MTX metabolism, possibly leading to unexpected adverse reactions. In this review, we focus on MTX, isoniazide and calcineurin inhibitors, and the implications of potential food-drug reactions in rheumatology, suggesting the important role of nutritional evaluations in RA patients.
24509936 Social persuasion in rheumatology: a randomized trial of testimonials on television in the 2014 Jul Multidisciplinary self-management programs are important in inflammatory arthritis as adjunctive treatment. Patients often have excuses as to why they do not attend these programs. The purpose of this study was to determine whether an intervention of televised testimonials from rheumatologists and allied health professionals increases attendance at a multidisciplinary education day for rheumatology patients seen in a large university hospital clinic. This was an RCT of intervention: playing televised interviews in the waiting room where rheumatology patients were seen versus no TV. There was a total of 6 months (3 months with and 3 without the televised interview playing). All eligible patients who attended the rheumatology outpatient clinic were then tracked to determine whether they attended a subsequent education day over the next 10 months. The sample size was calculated to have a 15% increase in attendance at the education days. There was a 20% increase in attendees at the multidisciplinary education days for patients who saw the televised testimonials. Sixty-three patients who viewed the testimonials (2.17% of 2,908) attended the education day compared to 39 who did not receive the intervention (1.80% of 2,168); however, the increase was not statistically significant (p = 0.36). Attendance of eligible patients increased using televised testimonials; however, the increase was not significant as the rates of attendance were still very low in both groups. Many eligible patients did not attend the program. Other interventions are necessary to encourage attendance in a multidisciplinary program.
23144446 Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheum 2013 Apr BACKGROUND: Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications. OBJECTIVE: To review published evidence on safety and efficacy of IL-6i in inflammatory diseases. METHODS: We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed http://www.clinicaltrials.gov. RESULTS: Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable. CONCLUSIONS: IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.
24161014 The mid-term outcome of total ankle arthroplasty and ankle fusion in rheumatoid arthritis: 2013 Oct 26 BACKGROUND: While arthrodesis is the standard treatment of a severely arthritic ankle joint, total ankle arthroplasty has become a popular alternative. This review provides clinical outcomes and complications of both interventions in patients with rheumatoid arthritis. METHODS: Studies were obtained from Pubmed, Embase and Web of Science (January 1980-June 2011) and additional manual search. INCLUSION CRITERIA: original clinical study, > 5 rheumatoid arthritis (population), internal fixation arthrodesis or three-component mobile bearing prosthesis (intervention), ankle scoring system (outcome). The clinical outcome score, complication- and failure rates were extracted and the methodological quality of the studies was analysed. RESULTS: 17 observational studies of 868 citations were included. The effect size concerning total ankle arthroplasty ranged between 1.9 and 6.0, for arthrodesis the effect sizes were 4.0 and 4.7. Reoperation due to implant failure or reoperation due to non-union, was 11% and 12% for respectively total ankle arthroplasty and arthrodesis. The methodological quality of the studies was low (mean 6.4 out of a maximum of 14 points) and was lower for arthrodesis (mean 4.8) as compared to arthroplasty (mean 7.8) (p = 0.04). CONCLUSIONS: 17 observational and no (randomized) controlled clinical trials are published on the effectiveness of arthroplasty or arthrodesis of the ankle in rheumatoid arthritis. Regardless of the methodological limitations it can be concluded that both interventions show clinical improvement and in line with current literature neither procedure is superior to the other.
25381975 Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid art 2014 Nov The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of hepatitis re-activation. This paper reports experience of using etanercept and adalimumab in 32 patients with RA and previous HBV or HCV infection. No cases of HBV or HCV reactivation were seen. In just over a fifth of patients, increased transaminases levels were seen, which were associated with concomitant use of disease-modifying antirheumatic drugs, isoniazid prophylaxis, or alcohol abuse. In our experience, anti-TNF-α therapy appears to be safe in RA patients with previous HBV or HCV infection, but monitoring remains necessary in these patients.
25290276 [Arthroscopy of the metacarpophalangeal joints]. 2014 Oct With the advancements in arthroscopic technique, arthroscopy has become feasible in most human joints, even those as small as the finger joints. The metacarpophalangeal joints are very well suited for arthroscopy and arthroscopic therapy. Good results have been reported on arthroscopic synovectomy of the metacarpophalangeal joints in rheumatoid arthritis. Osteochondral lesions in degenerative arthritis, loose bodies and foreign bodies can well be treated. Arthroscopic arthrolysis for capsular contracture and treatment of post-traumatic lesions have been performed successfully. The arthroscopic assistance in the treatment of intraarticular fractures and the capsular shrinkage for instability have been described. However, metacarpophalangeal joint arthroscopy has not been popularised up to now and its role in clinical practice remains to be established. Existing indications will be discussed with respect to our own experience.
22187054 Stevens-Johnson syndrome complicating adalimumab therapy in rheumatoid arthritis disease. 2013 May The efficacy of adalimumab, a fully human anti-tumor necrosis factor-α recombinant antibody, has dramatically improved the quality of life of patients with rheumatoid and psoriatic arthritis and Crohn's disease. Because it is fully human, one should not expect immune reactions to this molecule. Adverse reactions to adalimumab are limited mainly to injection site reactions and are very common. We, however, report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with rheumatoid arthritis (RA). In this case report, a 53-year-old woman with RA developed severe mucositis, peripheral rash and desquamation and fever concomitant with the fifth dose of 40 mg adalimumab. Infective etiologies were excluded. The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome. Severe skin reactions induced by TNF-α antagonists can be very serious, and prescribers need to be aware of the potential for the mucocutaneous adverse effects from the use of these agents, particularly due to the significant morbidity and mortality that are associated with SJS.
24687236 Efficacy and safety of certolizumab pegol in rheumatoid arthritis: meeting rheumatologists 2014 Apr Certolizumab pegol, a pegylated Fab' anti-tumour necrosis factor (TNF)-α agent, has shown efficacy in patients with rheumatoid arthritis (RA) unresponsive to previous treatment. In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease-modifying antirheumatic drug (DMARD), the efficacy of certolizumab pegol, as monotherapy or with methotrexate, was similar to that reported in other anti-TNF clinical studies, with 60% or fewer of patients achieving American College of Rheumatology 20% improvement in RA. Rapid clinical response was also seen, with significant differences evident at week 1, and efficacy maintained at study end and in open-label extensions. Adding certolizumab pegol to non-biological DMARDs is efficacious in other RA populations. In the CERTAIN study, certolizumab increased remission rates, prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA. In the REALISTIC study, rapid and consistent clinical responses were observed in a diverse group of anti-TNF-eligible RA patients representing those seen in clinical practice. In the RAPID studies, rapid and sustained reduction in RA signs and symptoms, inhibition of structural joint damage progression, and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate. Certolizumab pegol was generally well-tolerated in clinical trials, although long-term observational data are not yet available. Current data suggest that certolizumab pegol suits a 'treat to target' approach, providing rapid and sustained improvements in RA signs and symptoms, and beneficial effects on workplace and home productivity in patients with RA.
25433918 Methotrexate revisited: considerations for subcutaneous administration in RA. 2015 Feb Rheumatoid arthritis (RA) is associated with significant disability, morbidity, early mortality, and substantial financial burden. Despite newer antirheumatics, methotrexate (MTX) remains the most widely used disease-modifying antirheumatic drug. Subcutaneous (SC) MTX provides consistent, reliable delivery, with improved absorption and enhanced polyglutamization leading to increased response rates and fewer gastrointestinal side effects than oral MTX. Optimizing MTX with use of the SC formulation can improve outcomes and may delay or negate the need for costly biologics.
24409325 Serum levels of vasoactive intestinal peptide as a prognostic marker in early arthritis. 2014 OBJECTIVE: Suitable biomarkers are essential for the design of therapeutic strategies in personalized medicine. Vasoactive intestinal peptide (VIP) has demonstrated immunomodulatory properties in autoimmune murine and ex vivo human models. Our aim was to study serum levels of VIP during the follow-up of an early arthritis (EA) cohort and to analyze its value as a biomarker predicting severity and therapeutic requirements. METHODS: Data from 91 patients on an EA register were analyzed (76% rheumatoid arthritis (RA), 24% undifferentiated arthritis, 73% women, and median age 54 years; median disease duration at entry, 5.4 months). We collected per protocol sociodemographic, clinical, and therapeutic data. VIP levels were determined by enzyme immunoassay in sera harvested from the 91 patients (353 visits; 3.9 visit/patient) and from 100 healthy controls. VIP values below the 25(th) percentile of those assessed in healthy population were considered low. To determine the effect of independent variables on VIP levels, we performed a longitudinal multivariate analysis nested by patient and visit. A multivariate ordered logistic regression was modeled to determine the effect of low VIP serum levels on disease activity at the end of follow-up. RESULTS: VIP concentrations varied considerably across EA patients. Those fulfilling the criteria for RA had the lowest values in the whole sample, although no significant differences were observed compared with healthy donors. Disease activity, which was assessed using DAS28, inversely correlated with VIP levels. After a two-year follow-up, those patients with low baseline levels of VIP displayed higher disease activity and received more intensive treatment. CONCLUSION: Patients who are unable to up-regulate VIP seem to have a worse clinical course despite receiving more intense treatment. Therefore, measurement of VIP levels may be suitable as a prognostic biomarker.
24887337 Evaluation of etanercept dose reduction in patients with rheumatoid arthritis using pharma 2014 Sep OBJECTIVES: In this study, we attempt to explore the feasibility of alternative dosing regimens of etanercept in patients with rheumatoid arthritis (RA) using pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. METHODS: All data used for estimation of PK/PD model parameters were collected from previously published literatures. American College of Rheumatology (ACR) 20/50/70 response rate and a disease activity score in 28 joints (DAS28) was selected as the principal clinical endpoint for further PK/PD modeling. The cumulative AUC (area under the concentration-time curve) of etanercept for different dosing regimens was calculated based on the final PK model and was then linked to the time course of clinical endpoints. Ten different dosing regimens were simulated in this study. RESULTS: The PK model that best fit the serum concentration-time data for etanercept was a one-compartment model with first order absorption and elimination. Based on the PK/PD analysis, the relationship between the predicted cumulative AUC of etanercept to the ACR 20/50/70 response rate and DAS28 score was well characterized by Emax logistic and inhibitory Emax model, respectively. In our simulations, the following dosing regimens that are equally effective to current recommended dosage of 25 mg twice weekly (b.i.w.): (1) 25 mg once weekly (q.w.); (2) 50 mg every 2 weeks (q2w); (3) 25 mg b.i.w. for 3 months and 25 mg q2w thereafter; and (4) 50 mg q.w. for 3 months and 50 mg q2w thereafter. CONCLUSION: In this study, the clinical data was well described by the models developed, and several alternative dosing regimens were proposed. Further clinical studies in patients are still needed to confirm our findings.
23632195 Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone dama 2014 Apr OBJECTIVE: To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation. METHODS: Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3(-/-)) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3(-/-) and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells. RESULTS: Tyro3(-/-) mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3(-/-) mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3(-/-) mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner. CONCLUSIONS: These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.