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ID PMID Title PublicationDate abstract
27665099 Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease an 2017 Jan BACKGROUND: Therapeutic drug monitoring (TDM) of anti-TNF is increasingly used to manage inflammatory bowel diseases (IBD) and rheumatoid arthritis (RA). The cost-effectiveness of this strategy is debated. METHODS: All studies comparing the cost-effectiveness of a TDM-based strategy and an empirical dose management of anti-TNF in IBD or RA were screened. Studies were identified through the MEDLINE electronic database (up to July 2016), and annual international meeting abstracts were also manually reviewed. RESULTS: Seven studies were included: two randomized controlled trials (RCTs) enrolling 332 patients [247 Crohn's disease (CD) and 85 ulcerative colitis (UC)] and five modeling approaches. Four studies included only CD patients, one included both CD and UC patients, and two included only RA patients. Three studies compared the cost-effectiveness of the two strategies in patients with secondary infliximab (IFX) failure (dose-escalation strategy), one in patients in remission on optimized IFX (de-escalation strategy), one in patients starting adalimumab, and two in patients with clinical response to maintenance anti-TNF therapy. The two RCTs demonstrated that a TDM strategy led to major cost savings, ranging from 28 to 34 %. The three modeling approaches with regard to CD patients demonstrated cost savings ranging from $5396 over a 1-year period to €13,130 per patient at 5 years of follow-up. A TDM strategy also led to major cost savings in the two modeling approaches in RA patients. CONCLUSIONS: Available evidence indicates that a TDM strategy leads to major cost savings related to anti-TNF therapy in both IBD and RA patients, with no negative impact on efficacy.
27472516 Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients 2017 Mar OBJECTIVES: To evaluate the cost-effectiveness of biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: We used a state-transition model and parameters were determined from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study on 421 patients who had failed at least one DMARD and started either 1 of 4 bDMARDs (bDMARD group; adalimumab, etanercept, infliximab, and tocilizumab) or methotrexate (control group). bDMARD group was evaluated as two groups: sequence of any 1 of 4 bDMARDs with and without tocilizumab. The incremental cost-effectiveness ratios (ICERs) for bDMARD group were estimated using base-case analysis, probabilistic sensitivity analysis (PSA) and scenario sensitivity analyses. RESULTS: ICERs of bDMARD group with or without tocilizumab were $38,179 and $48,855, respectively. By PSA, these sequences had respective probabilities of 86.8% and 75.1% of falling below the assumed cost-effectiveness threshold of $50,000 in Japan. Scenario sensitivity analyses showed that the best population for initiating bDMARD was RA patients less than 50 years old with Japanese version of HAQ between 1.1 and 1.6 and using tocilizumab as the bDMARD. CONCLUSION: bDMARDs were cost-effective for RA patients based on a real-world setting in Japan.
28571501 CT-P13 in the treatment of rheumatoid arthritis. 2017 Jul The first biosimilar infliximab, CT-P13 infliximab-dyyb was approved in 2013 by the European Medicines Agency (EMA) and in 2016 by the United States Food and Drug Administration (FDA) and has been used for the treatment of rheumatoid arthritis (RA) for 4 years. Areas covered: CT-P13 with the three brand names on the market has highly similar efficacy and safety profiles but lower price than originator infliximab and are approved in more than 80 countries. One of the most important determinants of the implementation of CT-P13 in the treatment of RA is scientific evidence from clinical studies and real-world pharmacovigilance data. Here, we review all available clinical data supporting the similarity of CT-P13 to originator infliximab in its clinical efficacy and safety for the treatment of RA and related arthritis. In addition, we consider the role of CT-P13 in therapeutic strategies for RA treatment. Expert commentary: With its highly similar efficacy and safety profile to originator infliximab and its lower price, CT-P13 is expected to be very useful in RA treatment, whether it is applied earlier or switched from originator infliximab or other biologics. Future educational initiatives will be important to overcome misunderstandings about biosimilars and to improve the implementation of CT-P13.
27815104 Characteristic Magnetic Resonance Imaging Findings in Rheumatoid Arthritis of the Temporom 2017 Apr PURPOSE: The purpose of this study was to determine the characteristic magnetic resonance imaging (MRI) findings indicating bone and soft tissue involvement in patients with rheumatoid arthritis (RA) of the temporomandibular joints (TMJs). PATIENTS AND METHODS: Twenty-one patients with RA and TMJ pain who underwent MRI examination of the TMJs at the authors' hospital from August 2006 to December 2014 were included in this study. Twenty-two patients with normal TMJs who underwent MRI examination at the authors' hospital from November to December 2014 were included as controls. MRI findings were compared between the 2 groups. RESULTS: MRI findings of RA in the TMJ included 1) abnormal disc position (95.2%), 2) abnormal disc morphology (83.3%), 3) joint effusion (30.9%), 4) osseous changes in the mandibular condyle (83.3%), 5) synovial proliferation (pannus; 85.7%), 6) erosion of the articular eminence and glenoid fossa (9.52%), 7) deformity of the articular eminence and glenoid fossa (16.6%), 8) abnormal bone marrow signal in the mandibular condyle (83.3%), and 9) swelling of lymph nodes in the parotid glands (78.5%). The abnormal bone marrow signal and pannus in the mandibular condyle and lymph node swelling in the parotid glands were markedly more common in patients with RA than in controls. CONCLUSIONS: MRI findings of RA of the TMJs were characterized by bone and soft tissue involvement, including abnormal bone marrow signal of the mandibular condyle, pannus, and swelling of lymph nodes in the parotid glands. These characteristic MRI findings could be useful in detecting RA in the TMJ in a clinical situation.
28929342 Perception of Originator Biologics and Biosimilars: A Survey Among Belgian Rheumatoid Arth 2017 Oct BACKGROUND: Among patients and rheumatologists, current knowledge and perception of biosimilars in comparison with originator biologics is unknown. OBJECTIVES: The aim of this study was to investigate this knowledge and perception in Belgian rheumatologists and rheumatoid arthritis (RA) patients. METHODS: Anonymous web surveys were conducted in Belgian RA patients (n = 121) and rheumatologists (n = 41) during the period January-March 2016. The surveys covered topics on knowledge, similarity, price, preference, interchangeability, extrapolation and switching. Descriptive and statistical analyses of responses were performed. RESULTS: Familiarity with biosimilars was reported by 49% of patients, of whom 77% knew what biosimilars were. RA patients equally questioned the proven efficacy of originators and biosimilars in RA, as well as their side effects and suitability. Furthermore, RA patients questioned the safety of biosimilars more often than that of originators (35 vs. 20%, respectively; p = 0.0094). Rheumatologists, more so than patients, expressed concerns that there might be differences between originators and biosimilars in terms of quality, safety, and price (p = 0.0292, p < 0.0001, p = 0.0129, respectively). The opinions of rheumatologists on interchangeability and extrapolation of indications varied. The price of an originator contributed substantially to the medicine preference of rheumatologists (p = 0.0002), but not patients. CONCLUSION: Our study showed that rheumatologists, more so than patients, were convinced that there can be differences between originators and biosimilars. Despite safety being the major concern of patients, patients trusted their physician's decision to start on or switch to a biosimilar. The evolution of the uptake of biosimilars in Belgium might thus depend mainly on the perception of physicians.
28380117 Reactivation of cutaneous and mucocutaneous tegumentary leishmaniasis in rheumatoid arthri 2017 Apr 3 Rheumatoid arthritis (RA) is a chronic condition that is frequent in patients living in tropical areas exposed to leishmaniasis. RA therapy involves immunosuppressant drugs such as methotrexate (MTX), monoclonal antibodies (mAbs) and prednisone. We report an unusual presentation of cutaneous (CL) or mucocutaneous leishmaniasis (ML) in RA patients from an endemic area of leishmaniasis. A 51-year-old woman noted a cutaneous ulcer on her left ankle during MTX and prednisone RA therapy. Initially diagnosed as a venous stasis ulcer, the aspirate of the injury revealed the presence of Leishmania DNA. A 73-year-old woman presenting non-ulcerated, infiltrated and painful erythematous nodules inside her nostrils while receiving MTX, anti-TNF mAb, and prednisone for RA, had also the aspirate of injuries showing the presence of Leishmania DNA. Both patients healed after the therapy with liposomal amphotericin. The RA therapy has changed to low-dose prednisone, without further reactivation episodes. Both cases suggest that CL or ML can reactivate after administration of an immunosuppressant for RA treatment. Therefore, immunosuppressive treatments for RA should be carefully prescribed in patients from endemic areas or with a history of CL and ML.
28791873 Comparing biologic persistence and healthcare costs in rheumatoid arthritis patients initi 2017 Nov AIM: Comparing biologic persistence and healthcare costs between rheumatoid arthritis (RA) patients initiating first- or second-line subcutaneous abatacept, adalimumab, or etanercept. MATERIALS & METHODS: Retrospective, observational cohort study, which included adults with RA who initiated either of the three treatments between 29 July 2011 and 1 July 2015. Total healthcare costs were measured during baseline and follow-up. Biologic persistence was compared using multivariable Cox proportional hazards regression. RESULTS: Subcutaneous abatacept-treated patients had numerically lowest adjusted hazards of nonpersistence and increase from baseline in total healthcare costs. Sensitivity analyses measuring outcomes over an alternative follow-up definition produced consistent results. CONCLUSION: Abatacept-treated RA patients appeared to have the poorest health status yet often had the lowest increase from baseline in healthcare costs and longest duration of biologic persistence.
29280011 High burden of adverse events is associated with reduced remission rates in early rheumato 2018 Jun Adverse events (AEs) are common during disease-modifying antirheumatic drug (DMARD) treatment, but their influence on treatment results is unclear. We studied AEs in relation to disease activity in early rheumatoid arthritis (RA). Ninety-nine patients started intensive treatment with three conventional synthetic DMARDs (csDMARDs) and oral prednisolone, and were randomized to a 6-month induction treatment with infliximab or placebo. All AEs during the first 12 months of treatment were recorded. We scored each AE based on severity (scale 1-4) and defined the burden of AEs as the sum of these scores. Patients were divided into tertiles according to the burden of AEs. As outcomes, we assessed 28-joint disease activity score (DAS28) levels and remission rates at 12 and 24 months. Three hundred thirty-one AEs in 99 patients were reported, and 27 (8%) were categorized as severe or serious. Mean burden of AEs per patient was 5.4 ± 4.3. Seventy-nine AEs (24%) led to temporary (n = 52) or permanent (n = 27) csDMARD discontinuation. Of discontinuations, 1, 21, and 57 were detected in the first, second, and third tertiles, respectively. DAS28 remission rates decreased across tertiles at 12 months (94, 94, and 76%; p for linearity 0.029) and at 24 months (90, 86, and 70%; p for linearity 0.021). Mean DAS28 levels increased across tertiles at 12 months (1.5 ± 1.0, 1.7 ± 0.9, and 1.9 ± 1.2; p for linearity 0.021) and at 24 months (1.4 ± 0.8, 1.6 ± 1.0, and 1.9 ± 1.1; p for linearity 0.007). High burden of AEs is associated with higher disease activity and lower likelihood of remission in early RA.
29136635 Stroke among Rheumatoid Arthritis Patients: Does Age Matter? A Real-Life Study. 2017 BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that affects the joints and it is known to be associated with cardiovascular morbidity. However, the association between RA and stroke among different age groups has not been explored. The objective of our study was to evaluate the association between RA and stroke in different age strata. METHODS: Cross-sectional study, utilizing the database of Israel's largest healthcare provider. The proportion of stroke was compared between patients diagnosed with RA and age- and gender-matched controls. The study sample was divided into 2 age groups: young (≤65 years) and elderly (>65 years). Multivariable analysis was performed using logistic regression. RESULTS: The study included 11,782 RA patients and 57,973 age- and gender-matched controls. RA patients, primarily young, had more cardiovascular risk factors than controls. Stroke rates were significantly elevated among young RA patients in comparison with controls (3.74 vs. 2.20%, respectively, p < 0.001). In multivariate analysis, RA was found to be independently associated with stroke (OR 1.18, 95% CI 1.09-1.28). CONCLUSION: RA is independently associated with stroke, especially among RA patients under 65 years, for whom cardiovascular risk factors were more prominent. Physicians should advise RA patients to manage their risk factors strictly.
29148078 Soluble TAM receptor tyrosine kinases in rheumatoid arthritis: correlation with disease ac 2018 Apr The TAM receptor tyrosine kinases (TAM RTK) are a subfamily of receptor tyrosine kinases, the role of which in autoimmune diseases such as systemic lupus erythematosus has been well explored, while their functions in rheumatoid arthritis (RA) remain largely unknown. In this study, we investigated the role of soluble TAM receptor tyrosine kinases (sAxl/sMer/sTyro3) in patients with RA. A total of 306 RA patients, 100 osteoarthritis (OA) patients and 120 healthy controls (HCs) were enrolled into this study. The serum concentrations of sAxl/sMer/sTyro3 were measured by enzyme-linked immunosorbent assay (ELISA), then the associations between sAxl/sMer/sTyro3 levels and clinical features of RA patients were analysed. We also investigated whether sTyro3 could promote osteoclast differentiation in vitro in RA patients. The results showed that compared with healthy controls (HCs), sTyro3 levels in the serum of RA patients were elevated remarkably and sMer levels were decreased significantly, whereas there was no difference between HCs and RA patients on sAxl levels. The sTyro3 levels were correlated weakly but positively with white blood cells (WBC), immunoglobulin (Ig)M, rheumatoid factor (RF), swollen joint counts, tender joint counts, total sharp scores and joint erosion scores. Conversely, there were no significant correlations between sMer levels and the above indices. Moreover, RA patients with high disease activity also showed higher sTyro3 levels. In-vitro osteoclast differentiation assay showed further that tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts were increased significantly in the presence of sTyro3. Collectively, our study indicated that serum sTyro3 levels were elevated in RA patients and correlated positively with disease activity and bone destruction, which may serve as an important participant in RA pathogenesis.
29155868 Tocilizumab potentially prevents bone loss in patients with anticitrullinated protein anti 2017 Rheumatoid arthritis (RA) is associated with a high risk of osteoporosis and fracture. Interleukin (IL)-6 inhibitors may suppress osteoclast activation. Anticitrullinated protein antibody (ACPA) titers are inversely associated with bone mineral density (BMD). However, the differential effect of ACPA on bone turnover marker (BTM) and BMD changes after IL-6 inhibition remains unclear. This prospective study recruited patients with active RA with inadequate response to methotrexate or biologics. BMD was measured before and after 2-year tocilizumab (TCZ) treatment. Serum osteocalcin, N-terminal propeptide of type I collagen (P1NP), and C-terminal cross-linking telopeptide of type I collagen (CTX) levels were assessed at the baseline and after treatment. We enrolled 76 patients with RA (89.5% women, age: 57.2 ± 13.3 years) receiving TCZ. The 28-joint disease activity score was negatively correlated with BMD and T-scores of the lumbar spine and bilateral femoral neck. ACPA-positive patients had lower lumbar spine and femoral neck T-scores. After 2-year TCZ treatment, CTX levels significantly decreased (0.32 ± 0.21 vs. 0.26 ± 0.17, p = 0.038). Femoral neck BMD increased significantly (0.71 ± 0.22 vs. 0.69 ± 0.55, p = 0.008). Decreased CTX levels and improved BMD were observed only in ACPA-positive patients. After treatment, femoral neck BMD significantly increased only in patients receiving a glucocorticoid dose of ≥5 mg/day. Two-year TCZ treatment reduced bone resorption and increased femoral BMD in ACPA-positive patients. The net effects of glucocorticoids and IL-6 inhibition on BMD imply that strict inflammation control might affect bone metabolism.
28578493 Nailfold videocapillaroscopy results in patients with rheumatoid arthritis. 2017 Sep We aimed to analyse the nailfold capillaryscopy findings morphologically and examine their relationship with disease activity and demographic characteristics in patients with rheumatoid arthritis. In accordance with the 2010 ACR/EULAR classification criteria, 201 patients diagnosed with Romatoiad artrit (RA) and 50 healthy controls were included. We analysed capillaroscopic abnormalities such asmegacapillaries, haemorrhages, ramifications and avascular areas in patients affected with rheumatoid arthritis. The findings in our study are as follows: in 45.77% of the RA patients, there were nonspecific capillaryscopy findings. When compared to control group, the incidence of tortuosity, dilated capillary and bushy capillary was higher in RA patients (p values, respectively, 0.110, 0.330, 0.440 and 0.516). In RA patients with Raynaud's phenomenon, the incidence of nonspecific capillaryscopy findings was higher. While there is a weak relationship between tortuosity and the duration of disease, no significant relation was detected between capillaryscopy findings and parameters such as RF, anti-CCP positivity and disease activity score (DAS28). When compared to controls, we have detected that RA patients have more nonspecific capillaryscopic findings. We could not find a relationship between nonspecific capillaryscopic findings and RA'a clinical findings and laboratory parameters. There is a need for a long-term wider-scale follow-up study to investigate whether there is a capillaryscopic pattern that can be correlated with RA's clinical findings.
29075103 Amelioration of collagen-induced arthritis using antigen-loaded dendritic cells modified w 2017 Dendritic cells (DCs) play an important role in the initiation of autoimmunity in rheumatoid arthritis (RA); therefore, the use of DCs needs to be explored to develop new therapeutic approaches for RA. Here, we investigated the therapeutic effect of bovine type II collagen (BIIC)-loaded DCs modified with NF-κB decoy oligodeoxynucleotides (ODNs) on collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms. DCs treated with BIIC and NF-κB decoy ODNs exhibited features of immature DCs with low levels of costimulatory molecule (CD80 and CD86) expression. The development of arthritis in rats with CIA injected with BIIC + NF-κB decoy ODN-propagated DCs (BIIC-decoy DCs) was significantly ameliorated compared to that in rats injected with BIIC-propagated DCs or phosphate-buffered saline. We also found that the BIIC-decoy DCs exerted antiarthritis effects by inhibiting self-lymphocyte proliferative response and suppressing IFN-γ and anti-BIIC antibody production and inducing IL-10 antibody production. Additionally, antihuman serum antibodies were successfully produced in the rats treated with BIIC-decoy DCs but not in those treated with NF-κB decoy ODN-propagated DCs; moreover, the BIIC-decoy DCs did not affect immune function in the normal rats. These findings suggested that NF-κB decoy ODN-modified DCs loaded with a specific antigen might offer a practical method for the treatment of human RA.
29070529 Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA- 2018 Feb INTRODUCTION: The second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and smoking. Using a multiplex assay to detect multiple specific ACPA, we have investigated the fine specificity of individual ACPA responses and the biological impact of additional ACPA reactivity among anti-CCP2-negative patients. METHODS: We investigated 2825 patients with RA and 551 healthy controls with full data on anti-CCP2, HLA-DRB1* alleles and smoking history concerning reactivity against 16 citrullinated peptides and arginine control peptides with a multiplex array. RESULTS: The prevalence of the 16 ACPA specificities ranged from 9% to 58%. When reactivity to arginine peptides was subtracted, the mean diagnostic sensitivity increased by 3.2% with maintained 98% specificity. Of the anti-CCP2-negative patients, 16% were found to be ACPA positive. All ACPA specificities associated with SE, and all but one with smoking. Correction for arginine reactivity also conveyed a stronger association with SE for 13/16 peptides. Importantly, when all ACPA specificities were analysed together, SE and smoking associated with RA in synergy among ACPA positive, but not among ACPA-negative subjects also in the anti-CCP2-negative subset. CONCLUSIONS: Multiplexing detects an enlarged group of ACPA-positive but anti-CCP2-negative patients with genetic and environmental attributes previously assigned to anti-CCP2-positive patients. The individual correction for arginine peptide reactivity confers both higher diagnostic sensitivity and stronger association to SE than gross ACPA measurement.
29221598 The role of ACPAs in at-risk individuals: Early targeting of the bone and joints. 2017 Feb Autoimmunity precedes inflammation in patients with rheumatoid arthritis (RA), opening the possibility to search for early changes in the tissue preceding the onset of systemic inflammation. Autoantibodies are important and early drivers of bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor (RF) and antibodies recognizing modified (citrullinated) proteins have been used as diagnostic markers for RA over many years. Their role as pathogenic players, however, has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel association between autoimmunity and bone. These developments have allowed the unraveling of the underlying mechanisms, which are responsible for the well-known clinical observation that anti-citrullinated protein antibodies and RF are associated with a more severe disease course. Furthermore, these mechanisms also explain the onset of inflammation in the joints of RA patients.
28288327 Parvovirus B19 infection modulates the levels of cytokines in the plasma of rheumatoid art 2017 Aug BACKGROUND: Parvovirus B19 (B19V) infection is associated with various autoimmune diseases. We investigated the levels of pro-inflammatory (IFNᵧ, TNFα, IL-2, IL-12) and anti-inflammatory (IL-4, IL-10) cytokines in the plasma of B19V DNA positive (B19(+)) and negative (B19(-)) rheumatoid arthritis (RA) patients in comparison with the control group (healthy persons). METHODS: Blood samples were collected from 118 patients with RA and 49 healthy voluntaries. B19V sequence was determined in whole blood and cell-free plasma DNA by nested PCR. The levels of cytokines in the plasma and cell culture medium from Concanavalin A (ConA) or B19V VP1 protein stimulated PBMC were determined by ELISA. RESULTS: The levels of IL-4, IL-10, IL-12, IL-2 and TNFα were higher in plasma of RA patients in comparison with control persons. B19(+) controls and RA patients had lower levels of IFNᵧ in comparison with B19(-) controls and RA patients. Within RA patients the plasma levels of IFNᵧ were lower in patients with low RA disease activity or remission. Plasma level of IL-4 was increased and IL-10 level was decreased in B19(+) RA patients in comparison with B19(-) RA patients and did not differ between B19(+) and B19(-) controls. B19V infection did not affect plasma levels of IL-12, IL-2, and TNFα. ConA and B19 VP1 protein stimulated PBMC from RA patients produced less IFNᵧ than stimulated PBMC from the healthy controls. CONCLUSIONS: B19V infection could differently modulate the amount of cytokines in the plasma of healthy persons and RA patients. Decreased production of IFNᵧ and raised level of plasma IL-4 in RA patients could lower antiviral clearance.
27419921 Chronic Conditions and Self-Reported Health in a Medicare Advantage Plan Population. 2017 Apr Self-reported changes in physical and mental health by members are an important dimension by which the quality of a Medicare Advantage (MA) plan is rated by the Centers for Medicare & Medicaid Services. To better target their interventions, MA plans need a better understanding of what observed characteristics-including clinical health conditions-predict self-reported changes in physical and mental health. This study explored how one MA plan's survey of participants' responses regarding changes in physical and mental health is associated with a set of chronic conditions as well as sociodemographic characteristics. Multinomial logistic regressions were used to examine the influence of 9 chronic conditions and age, sex, race, education, dual eligibility status (Medicare/Medicaid eligible), marital and living status, and assistance with survey completion on changes in patient-reported physical and mental health. Six conditions-dementia (P < 0.001), diabetes (P = 0.003), congestive heart failure (P = 0.002), cerebrovascular disease (P = 0.001), coronary artery disease (CAD) (P < 0.001), and rheumatoid arthritis (P < 0.001)-were associated with self-reported worsening of overall physical health. Four conditions-dementia (P < 0.002), diabetes (P = 0.047), CAD (P = 0.001), and decubitus ulcers (P = 0.033)-were associated with self-reported worsening of overall mental health. Females, married respondents, and those needing assistance with survey completion were more likely to report worsening of their mental health. Enrollees older than age 65 actually were less likely to report worsening of overall mental health. Findings provide insight into which members may be more susceptible to reporting that their physical or mental health is worsening.
29137196 High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Ris 2017 Nov 13 Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR. The overall transcriptional activity in WAT was significantly higher in patients with CVR and was presented by higher serum levels of WAT products leptin, resistin and IL-6 (all, p < 0.001). CVR was associated with high WAT-specific transcription of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor NF-kappa-B p65 subunit (RELA), and with high transcription of serine-threonine kinase B (AKT1) in leukocytes. These findings suggest Interleukin 6 (IL-6) and leptin take part in WAT-specific activation of STAT3. The binary logistic regression analysis confirmed an independent association of CVR with IL-6 in serum, and with STAT3 in WAT. The study shows an association of CVR with transcriptional activity in WAT in female RA patients. It also emphasizes the importance of STAT3 regulatory circuits for WAT-related CVR in RA.
27749216 On the history of gout: paleopathological evidence from the Medici family of Florence. 2017 Mar OBJECTIVES: Throughout history, gout has been referred to as the "disease of the kings", and has been clearly associated with the lifestyle of the aristocratic social classes. According to the written sources, several members of the famous Medici family of Florence suffered from an arthritic disease that contemporary physicians called "gout". A paleopathological study carried out on the skeletal remains of some members of the family, exhumed from their tombs in the Church of San Lorenzo in Florence, offered a unique opportunity to directly investigate the evidence of the arthritic diseases affecting this elite group. METHODS: The skeletal remains of several members of the family were examined macroscopically and submitted to x-ray investigation. RESULTS: The results of the study allowed us to ascertain that the so-called "gout of the Medici" should be considered the clinical manifestation of three different joint conditions: diffuse idiopathic skeletal hyperostosis, rheumatoid arthritis and uratic gout. In particular, uric acid gout was diagnosed in the Grand Duke Ferdinand I (1549-1609). Recently, a new case of this disease was diagnosed in Anton Francesco Maria (1618-1659), a probable illegitimate member of the family. CONCLUSIONS: With this new case, uratic gout was observed in 2 out of 9 adult males, leading to suppose that the disease should have been a common health problem within the family. The aetiology of the disease has to be searched in environmental factors, since both historical and paleonutritional studies demonstrated that the diet of this aristocratic court was rich in meat and wine.
28969588 Design considerations and analysis planning of a phase 2a proof of concept study in rheuma 2017 Oct 2 BACKGROUND: It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. METHODS: The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. RESULTS: It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. CONCLUSIONS: In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.