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ID PMID Title PublicationDate abstract
27589009 The underlying inflammatory chronic disease influences infliximab pharmacokinetics. 2016 Oct Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.
27350088 Serum thymosin α 1 levels in patients with chronic inflammatory autoimmune diseases. 2016 Oct Thymosin alpha 1 (Tα1) is a powerful modulator of immunity and inflammation. Despite years of studies, there are a few reports evaluating serum Tα1 in health and disease. We studied a cohort of healthy individuals in comparison with patients affected by chronic inflammatory autoimmune diseases. Sera from 120 blood donors (healthy controls, HC), 120 patients with psoriatic arthritis (PsA), 40 with rheumatoid arthritis (RA) and 40 with systemic lupus erythematosus (SLE), attending the Transfusion Medicine or the Rheumatology Clinic at the Policlinico Tor Vergata, Rome, Italy, were tested for Tα1 content by means of a commercial enzyme-linked immunosorbent assay (ELISA) kit. Data were analysed in relation to demographic and clinical characteristics of patients and controls. A gender difference was found in the HC group, where females had lower serum Tα1 levels than males (P < 0·0001). Patients had lower serum Tα1 levels than HC (P < 0·0001), the lowest were observed in PsA group (P < 0·0001 versus all the other groups). Among all patients, those who at the time of blood collection were taking disease-modifying anti-rheumatic drugs (DMARD) plus steroids had significantly higher Tα1 levels than those taking DMARD alone (P = 0·044) or no treatment (P < 0·0001), but not of those taking steroids alone (P = 0·280). However, whichever type of treatment was taken by the patients, serum Tα1 was still significantly lower than in HC and there was no treatment-related difference in PsA group. Further prospective studies are necessary to confirm and deepen these observations. They might improve our understanding on the regulatory role of Tα1 in health and disease and increase our knowledge of the pathogenesis of chronic inflammatory autoimmune diseases.
27013892 The pro-apoptotic effects of TIPE2 on AA rat fibroblast-like synoviocytes via regulation o 2016 TIPE2, also known as TNFAIP8L2, a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, is known as an inhibitor in inflammation and cancer, and its overexpression induces cell death. We examined the role of TIPE2 with respect to adjuvant arthritis (AA)-associated pathogenesis by analyzing the TIPE2 regulation of death receptor (DR5)-mediated apoptosis in vitro. The results showed that TIPE2 was detected in normal fibroblast-like synoviocytes (FLSs), but scarcely observed in AA-FLSs. Therefore, recombinant MIGR1/TIPE2(+/+) and control MIGR1 lentivirus vectors were transfected to AA-FLSs, which were denoted as TIPE2(+/+)-FLSs and MIGR1-FLSs, respectively. Our results showed that TIPE2(+/+)-FLSs were highly susceptible to ZF1-mediated apoptosis, and ZF1 was our own purification of an anti-DR5 single chain variable fragment antibody. Under the presence of TIPE2, the expression of DR5 was significantly increased compared with that of the MIGR1-FLS group. In contrast, the level of phosphorylated nuclear factor-kappa B (pNF-κB) was lower in the TIPE2(+/+)-FLS group treated with ZF1, whereas the activity of caspase was higher. Moreover, the rate of apoptosis in the TIPE2(+/+)-FLS group, which was pretreated with caspase inhibitor Z-VAD-FMK, was significantly decreased. In contrast, the apoptosis occurrence in the MIGR1-FLS group increased significantly with the pretreatment of the NF-κB inhibitor Bay. These results indicated that TIPE2 increased the apoptosis of AA-FLSs by enhancing DR5 expression levels, thereby promoting the activation of caspase and inhibiting the activation of NF-κB in AA-FLSs. TIPE2 might potentially act as a therapeutic target for rheumatoid arthritis.
27912793 Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lup 2016 Dec 3 BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data. METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available. RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients. CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.
27660855 Discovery of Orally Efficacious Phosphoinositide 3-Kinase δ Inhibitors with Improved Meta 2016 Oct 13 Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.
26297841 A new ursane triterpenoic acid and other potential anti-inflammatory and anti-arthritic co 2015 Nov 4 OBJECTIVE: Vitellaria paradoxa (shea tree) is used in traditional medicine for the treatment of various ailments, including, inflammation and fever. Therefore the present research investigates the anti-inflammatory and anti-rheumatic effects of V. paradoxa stem bark extracts in rats and the isolation and characterization of its active constituents. METHODS: The anti-inflammatory activity of ethyl acetate extract of V. Paradoxa (VPEE) was evaluated by use of the carrageenan-induced paw oedema model in rats. Moreover, rheumatoid arthritis (RA) was induced by injection of Freund's Completed Adjuvant (FCA) into the subplantar surface of the hind paw of the male Wistar rats. Paw volume was measured plethysmometrically. Joint swelling was measured using electronic vernier caliper. Hot plate test was used to assess the effect of VPEE on hyperalgesia while open field was used to assess the locomotors activity. The relative weight of spleen, liver and thymus was obtained as well as some haematological parameters. Tibiotarsal joint was extracted for histopathology under light microscope. Chemical analysis was carried out by high resolution mass spectrometry and one and two-dimensional NMR techniques. RESULTS: LC-MS analysis of the EtOAc extract revealed the presence of a new triterpenoid and several known compounds. The structure of the novel compound was elucidated by means of LC-MS and selected 1D and 2D-NMR experiments. The biological effects of ethyl acetate (VPEE), methanol (VPME) and water extracts (VPAE) of V. paradoxa were tested on carrageenan model of acute inflammation and FCA-induced rheumatoid arthritis animal model. In the carrageenan-induced inflammation, VPEE (150 mg/kg) significant (66.67%) inhibited the first (after 1h) and the second phase (4-6h) of edema formation. On the Complete Freund's adjuvant-induced rheumatoid arthritis, VPEE at the same dose showed a significantly protective effect. On days 19-28th of treatment, the maximum inflammatory percentage was between 9.60 and 8.91% for the VPEE compared to 30.91-24.29% for the controls. All the extracts significantly reduced the score of arthritis but the maximal reduction was obtained with the VPEE on day 24th of the experimentation. The altered haematological parameters in the arthritic rats were significantly recovered to near normal by the treatment with VPEE at the dose of 150 mg/kg. Further histological studies revealed the anti-arthritic activity by preventing cartilage destruction of the arthritic joints of adjuvant arthritic rats. The spleen hypertrophy induced by the FCA was also significantly inhibited. CONCLUSION: These findings provide pharmacological basis for the application of the VPEE in inflammatory disorders.
25870507 Cardiac MRI findings of endomyocardial fibrosis (Loeffler's endocarditis) in a patient wit 2015 Apr Loeffler's endocarditis and cardiac manifestations of the hypereosinophilic syndrome (HES) are rare and difficult to diagnose. We report a case of in a 36 year-old female with a history of rheumatoid arthritis with disabling dyspnea. The transthoracic echocardiogram demonstrated normal systolic cardiac functions and a left ventricular apical thrombus. However, using cardiovascular magnetic resonance (CMR) with inversion-recovery (IR) delayed enhancement, and cine steady-state free precession (SSFP) sequences, we were able to clearly demonstrate endocardial fibrosis, tissue inflammation, apical ventricular hypertrophy, and LV thrombus that correlate with clinical findings. We believe cardiac MRI is more useful than transthoracic echocardiography in the diagnosis and management of HES and ultimately it obviated the need for biopsy to confirm the diagnosis.
27302209 Personalized medicine. Closing the gap between knowledge and clinical practice. 2016 Aug Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.
26420996 Radiosynovectomy of Proximal Interphalangeal Joint Synovitis in Rheumatoid Arthritis Treat 2015 Sep Rheumatoid arthritis (RA) is a chronic disease that is mainly characterized by the asymmetric erosive synovitis, particularly affecting peripheral joints. Radiation synovectomy or radiosynovectomy (RSV), also known as radiosynoviorthesis was first described in 1950's as an adjuvant treatment for RA. RSV is based on the irradiation of the joint synovium by the intra-articular administration of various β-emitting radiopharmaceuticals. As a generator-produced β-emitting radionuclide, the importance of rhenium-188 (Re-188) for radionuclide therapy is increasing rapidly. There are previous reports which used Re-188 tin colloid in knee joint synovitis, but use of Re-188 tin colloid in small joint is not yet reported. We describe the use of Re-188 tin colloid in a 45-year-old female who presented with right 4(th) proximal interphalangeal joint synovitis due to rheumatoid arthritis.
27900570 Concomitant Use of Statins in Tocilizumab-Treated Patients with Rheumatoid Arthritis: A Po 2017 Jun INTRODUCTION: Patients with rheumatoid arthritis (RA) have decreased survival because of increased cardiovascular risk compared with the general population, and treatment with tocilizumab (TCZ) has been shown to increase lipid levels; however, the relationship between lipids and cardiovascular risk is unknown. This post hoc analysis expanded on previously reported 24-week results by characterizing statin use and subsequent changes in lipid parameters in patients with RA treated with intravenous or subcutaneous TCZ (TCZ-IV or TCZ-SC) over 2 years of treatment. METHODS: Data were collected from patients with moderate to severe active RA who received ≥1 dose of the study drug in seven international, randomized, double-blind, controlled phase 3 and 4 clinical trials of TCZ-IV or TCZ-SC. Lipid levels and safety events were assessed over 2 years of treatment. Data were summarized for all pooled treatment groups of the intention-to-treat populations in the TCZ-IV and TCZ-SC studies, and results were stratified by concomitant statin use. RESULTS: Data from this descriptive, retrospective, pooled analysis indicated that statins can stabilize lipid levels without a clinically significant increase in adverse events. Approximately 30% of patients in the TCZ treatment arms who never received a statin demonstrated a shift in low-density-lipoprotein cholesterol (LDL-C) from <130 mg/dl at baseline to ≥130 mg/dl at 2 years. However, despite the increased potential cardiovascular risk, <15% of patients with LDL-C ≥100 mg/dl and <35% of patients with a total cholesterol:high-density-lipoprotein cholesterol ratio >5 at 2 years were receiving concomitant statins. CONCLUSION: Concomitant statin use attenuated TCZ-mediated lipid increases; however, a large proportion of TCZ-treated patients potentially at risk of cardiovascular disease were untreated. These findings highlight the need for better understanding of potential risk associated with TCZ-mediated lipid elevations as well as implementation of RA-specific guidelines on the recognition and management of elevated risk of cardiovascular events in patients with RA. FUNDING: F. Hoffmann-La Roche, Ltd.
27774824 Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1. 2017 Feb Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts. The authors have ordered recent patents according to the primary applicant's name, with part 1 covering A through to I. Expert opinion: Inhibition of JAK-family kinases is an area of growing interest, catalysed by the maturity of data on marketed inhibitors ruxolitinib and tofacitinib in late stage clinical trials. Many applicants are pursuing traditional fast-follower strategies around these inhibitors, with a range of chemical strategies adopted. The challenge will be to show sufficient differentiation to the originator compounds, since dose limiting toxicities with such agents appear to be on target and mechanism-related and also considering that such agents may be available as generic compounds by the time follower agents reach market.
27683525 The Clinical Value of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels in A 2016 Apr The assessment of the general inflammatory condition of patients with autoimmune connective tissue disorders (ACTD) is a major challenge. The use of traditional inflammatory markers including CRP-levels and erythrocyte sedimentation rate (ESR) is limited by several preanalytical factors and their low specificities. Soluble urokinase plasminogen activator receptor (suPAR) is one of the novel candidate markers that is increasingly used in immune mediated disorders. In our studies we compared suPAR levels of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ankylosing spondylitis with those of healthy controls. suPAR provided valuable clinical information on disease activity in RA, SLE and SSc. We identified a subgroup of remitted RA patients, who presented still clinical symptoms of inflammatory activity which correlated to high plasma suPAR (while ESR and CRP were normal). In SLE we established specific suPAR cut-off values that support the discrimination between patients with high and those with moderate SLE activity. In patients with SSc suPAR correlated with objective measures of lung and other complications. In the majority of ACTDs including SLE, SSc or RA, suPAR is seemingly a good biomarker that would provide valuable clinical information. However, before the introduction of this novel parameter in laboratory repertoire important issues should be elucidated. These include the establishment of appropriate and disease specific cutoff values, clarification of interfering preanalytical values and underlying conditions and declaration of age- and gender-specific reference ranges.
26903770 Formulation and evaluation of ileo-colonic targeted matrix-mini-tablets of Naproxen for ch 2016 Jan In this present research work, the aim was to develop ileo-colonic targeted matrix-mini-tablets-filled capsule system of Naproxen for chronotherapeutic treatment of Rheumatoid Arthritis. So Matrix-mini-tablets of Naproxen were prepared using microsomal enzyme dependent and pH-sensitive polymers by direct compression method which were further filled into an empty HPMC capsule. The compatibility was assessed using FT-IR and DSC studies for pure drug, polymers and their physical mixtures. The prepared batches were subjected to physicochemical studies, drug content estimation, in-vitro drug release and stability studies. When FTIR and DSC studies were performed, it was found that there was no interaction between Naproxen and polymers used. The physicochemical properties of all the prepared matrix-mini-tablets batches were found to be in limits. The drug content percentage in the optimized formulation F18 was found to be 99.24 ± 0.10%. Our optimized matrix-mini-tablets-filled-capsule formulation F18 releases Naproxen after a lag time of 2.45 ± 0.97 h and 27.30 ± 0.86%, 92.59 ± 0.47%, 99.38 ± 0.69% at the end of 5, 8, 12 h respectively. This formulation was also found to be stable as per the guidelines of International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use. Thus, a novel ileo-colonic targeted delivery system of Naproxen was successfully developed by filling matrix-mini-tablets into an empty HPMC capsule shell for targeting early morning peak symptoms of rheumatoid arthritis.
26381536 Cellular misfolded proteins rescued from degradation by MHC class II molecules are possibl 2015 Nov The major function of major histocompatibility complex (MHC) class II molecules is the presentation of peptide antigens to helper T cells. However, when misfolded proteins are associated with MHC class II molecules in the endoplasmic reticulum, they are transported to the cell surface by MHC class II molecules without processing to peptides. Of note, misfolded proteins complexed with MHC class II molecules are specifically recognized by autoantibodies produced in patients with autoimmune diseases such as rheumatoid arthritis and antiphospholipid syndrome. Furthermore, autoantibody binding to misfolded proteins complexed with MHC class II molecules is associated with the susceptibility to autoimmune diseases conferred by each MHC class II allele. Therefore, misfolded proteins rescued from degradation by MHC class II molecules may be recognized as 'neo-self' antigens by the immune system and be involved in the pathogenicity of autoimmune diseases.
25653505 Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoi 2015 OBJECTIVE: To examine reasons why rheumatoid arthritis patients discontinued subcutaneous (SQ) anti-tumor necrosis factor (anti-TNF) treatment in the past 12 months, so as to help inform successful, uninterrupted therapy. METHODS: Data were collected in March and April 2011 using self-reported, internet-based questionnaires. Study inclusion criteria comprised: rheumatoid arthritis diagnosis; discontinuation of SQ anti-TNF medication (adalimumab, certolizumab, etanercept, or golimumab) within the past 12 months; aged ≥18 years; United States residency; and consent to participate. Patients reported primary and other reasons for discontinuation of their most recently discontinued anti-TNF. RESULTS: Questionnaires from 250 patients were analyzed; 72.8% were female, 80.8% were white, and median age was 51 years. Patients had discontinued etanercept (n=109), adalimumab (n=98), certolizumab (n=24), or golimumab (n=19) within the past 12 months. When prompted about their primary reason for discontinuation, lack of effectiveness (40.8%) was cited most often, followed by injection experience (18.4%). Combining prompted primary and other reasons for discontinuation, 60.8% of patients reported lack of effectiveness, while 40.8% reported injection experience, which included: pain/burning/discomfort after injection (14.4%); pain/burning/discomfort during injection (13.2%); injection reactions such as redness/swelling after injection (12.4%); dislike of self-injection (11.6%); dislike of frequency of injection (10.4%); and fear of injection/needles (6.8%). CONCLUSION: From the patient perspective, there are unmet needs with regard to the effectiveness and injection experience associated with SQ anti-TNF medications, which may lead to discontinuation. Treatment options with a better injection experience may address these needs. These results demonstrate the importance of including the patient perspective when making prescribing decisions or payer access and coverage decisions.
25185723 An assessment of treatment history and its association with clinical outcomes and relapse 2015 Apr BACKGROUND: Studies of pemphigus vulgaris and foliaceus patients treated with rituximab have used several different dosing protocols. Likewise, patients' clinical history varies in the length of the disease prior to initiation of rituximab, previous immunosuppressants used and adjuvants used during rituximab treatment. OBJECTIVE: We sought to assess clinical factors associated with improved outcomes and a greater duration from last dose of rituximab to time of relapse in patients responding to a single cycle of rituximab. METHODS: We retrospectively evaluated published cases of pemphigus patients treated with a single cycle of rituximab. RESULTS: One hundred and fifty-five patients were evaluated. An increased number of months with disease before receiving treatment were associated with failure to achieve complete remission. Patients treated using the low-dose rheumatoid arthritis protocol (2 × 500 mg) experienced a lower rate of complete response and a decrease in the time to relapse. Patients treated using the standard lymphoma protocol (375 mg/m(2) × 4 weeks) demonstrated improved time to relapse. There was no difference seen in the rate of patients reaching complete response in patients treated with the standard lymphoma protocol vs. the standard rheumatoid arthritis protocol (1000 mg × 2). The use of adjuvant plasma exchange or immunoadsorption was associated with an increase in the time to relapse. CONCLUSION: Based on these observations, the low-dose rheumatoid arthritis protocol should not be recommended due to the inferior clinical response and shortened time to relapse.
27721903 Combination leflunomide and methotrexate in refractory rheumatoid arthritis: a biologic sp 2016 Oct BACKGROUND: In resource-constrained settings where biologic agents are not widely available, there are limited therapeutic options for patients with rheumatoid arthritis (RA) refractory to other synthetic disease modifying antirheumatic (DMARD) therapies. The aim of this study is to evaluate the effectiveness and safety of leflunomide (LEF) with methotrexate (MTX) in refractory RA. METHODS: A retrospective record review of adult RA patients treated with LEF/MTX. Demographic details, adverse reactions, and the 3-variable 28 joint disease activity score (DAS28-3) were recorded at initiation of LEF/MTX therapy, and after 4 and 12 months of treatment. RESULTS: Of 194 patients, most were middle-aged seropositive Black African females, with established disease [mean (standard deviation, SD) disease duration 9.4 (8.2) years] and time on previous DMARDs of 7.0 (5.5) years. Before adding LEF, the mean (SD) dose of MTX was 21.7 (3.5) mg/week, and 87.6% of patients used low dose oral corticosteroids. A good or moderate EULAR response was achieved by 44% and 42% of patients, and the retention rate was 71%. Major infections were seen in 6 patients: comprising 2 deaths, 3 cases of leucopaenia and septicaemia and 1 case of tuberculosis. Hepatotoxicity (n = 3), intolerable gastrointestinal symptoms (n = 3), and hypertension (n = 17) were the most common problems. Predictors of remission or low disease activity at 12 months was a baseline DAS28-3 ⩽ 5.5 [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.1-5.6; p = 0.01]. CONCLUSIONS: LEF/MTX was effective in the majority of patients in this cohort of mainly Black African women who failed other combination synthetic DMARDs, particularly in those with moderate disease activity at the time of addition of LEF. Infections and hypertension were important complications. In a setting where biologic DMARDs are not readily accessible, the combination of LEF/MTX is a cost-effective approach.
27651924 Impact of intensive treatment and remission on health-related quality of life in early and 2016 OBJECTIVES: To establish if using intensive treatment to reduce synovitis and attain remission in active rheumatoid arthritis (RA) improves all aspects of health-related quality of life (HRQoL). METHODS: A secondary analysis of two randomised clinical trials (CARDERA and TACIT) was undertaken. CARDERA randomised 467 patients with early active RA to different disease-modifying antirheumatic drug (DMARD) regimens, including high-dose tapering corticosteroids. TACIT randomised 205 established patients with active RA to combination DMARDs (cDMARDs) or tumour necrosis factor-α inhibitors (TNFis). Short-Form 36 (SF-36) measured HRQoL across eight domains, generating physical (PCS) and mental (MCS) component summary scores. Linear regression evaluated 6-month intensive treatment impacts. Mean SF-36 scores, stratified by end point disease activity category, were compared with age/gender-matched population scores. RESULTS: In CARDERA, intensive corticosteroid treatment gave significantly greater improvements in PCS but not MCS scores relative to placebo. In TACIT, all eight SF-36 domains had improvements from baseline exceeding minimal clinically important differences with cDMARDs and TNFis. Significantly greater improvements with TNFi relative to cDMARDs were reported in PCS only (p=0.034), after adjusting for covariates. Remission provided the best SF-36 profiles, but scores in physical functioning, role physical and general health in both trials remained below normative values. Patient global assessment of disease activity had a greater association with HRQoL than other disease activity score (DAS28) components. CONCLUSIONS: Intensive corticosteroid treatment in early RA improves physical but not mental health, relative to placebo. In established RA, cDMARDs and TNFi provide similar improvements in HRQoL. As remission optimises but fails to normalise HRQoL, a focus on treatment strategies targeting HRQoL is required. TRIAL REGISTRATION NUMBERS: CARDERA was registered as ISRCTN 32484878. TACIT was registered as ISRCTN 37438295; pre-results.
27532898 Integration of known DNA, RNA and protein biomarkers provides prediction of anti-TNF respo 2016 Sep OBJECTIVE: In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-art precision medicine will benefit RA patients. METHODS: We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high-throughput RNA sequencing, DNA genotyping, extensive proteomics and flow cytometry measurements, as well as comprehensive clinical phenotyping. Literature review identified 2 proteins, 52 single-nucleotide polymorphisms (SNPs) and 72 gene-expression biomarkers that had previously been proposed as predictors of TNF inhibitor response (∆DAS28-CRP). RESULTS: From these published TNFi biomarkers we found that 2 protein, 2 SNP and 8 mRNA biomarkers could be replicated in the 59 TNF initiating patients. Combining these replicated biomarkers into a single signature we found that we could explain 51% of the variation in ∆DAS28-CRP. This corresponds to a sensitivity of 0.73 and specificity of 0.78 for the prediction of three month ∆DAS28-CRP better than -1.2. CONCLUSIONS: The COMBINE biobank is currently the largest collection of multi-omics data from RA patients with high potential for discovery and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort.
27006728 Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rhe 2016 BACKGROUND: Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. OBJECTIVE: To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. METHODS: In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. RESULTS: In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. CONCLUSION: After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. TRIAL REGISTRATION: Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354.