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ID PMID Title PublicationDate abstract
21466765 Tumour necrosis factor-α inhibitors are glucocorticoid-sparing in rheumatoid arthritis. 2011 Apr INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease with autoimmune traits of unknown aetiology which primarily affects synovial joints. Glucocorticoids (GCs) are still widely used in RA treatment despite the expanding use of targeted and very efficient agents. The objective of this study was to assess the impact of treatment with tumour necrosis factor-α inhibitors (TNFi) on GC utilization in real-life practice among Danish RA patients. MATERIAL AND METHODS: The DANBIO registry is a nationwide rheumatologic database which collects demographic and clinical data. This retrospective study included RA outpatients from a tertiary rheumatologic department recruited from the DANBIO registry who initiated their first TNFi treatment between January 2000 and February 2010 (n = 171). GC dosing during the year before and the year after TNFi initiation were compared. Patients acted as their own control. RESULTS: The median daily prednisolone dose was significantly decreased after initiation of TNFi treatment (p < 0.01). At TNFi initiation, 78 patients (46%) received prednisolone compared with 53 (31%) by the end of follow-up. After TNFi initiation, 30 patients (38%) discontinued prednisolone and in 34 (44%) prednisolone dose was reduced. Similarly, the number of GC injections decreased significantly at 13, 26 and 52 weeks following TNFi initiation (p < 0.01). CONCLUSION: GC utilization is significantly reduced after initiation of TNFi treatment. Among patients on prednisolone at TNFi onset, prednisolone was withdrawn in one third and the dose was reduced in nearly half. Furthermore, the need for GC injections decreased.
21232553 Remission of asthma: The next therapeutic frontier? 2011 Apr Asthma treatment goals focus on disease control rather than remission as a therapeutic aim. This is in contrast to diseases where remission is frequently discussed and has well-defined criteria. In this review, we consider the similarities and differences between remission in asthma and another chronic inflammatory disease, rheumatoid arthritis, where new therapies have made remission a realistic treatment goal. Clinical remission of asthma is often defined as prolonged absence of asthma symptoms without requirement for medication while others insist on the demonstration of normal lung function and airway responsiveness. Even in those who develop a symptomatic remission of asthma, persistent physiological abnormalities and airway inflammation are common. There is a clear need to develop a precise, internationally accepted, definition of asthma remission that can be used as a therapeutic endpoint in studies of new asthma treatments. Spontaneous remission of asthma symptoms is relatively common, especially during adolescence. It is more likely in males, those with mild symptoms and normal lung function and in those who quit smoking, and may be linked to normalisation of immune function. Remission is less likely in severe asthma, atopy, eosinophilia, airflow obstruction, continued smoking and weight gain. Studies of spontaneous remissions may provide insight into how remission might be induced with therapy. Remission is not identical to cure, there remains a risk of subsequent symptomatic relapse of asthma and there is little evidence that current asthma treatments can induce remission. Long-term remission should be regarded as the next therapeutic frontier in asthma management.
22190977 Notch signaling mediates TNF-α-induced IL-6 production in cultured fibroblast-like synovi 2012 It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA). The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs) from RA. Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by a γ-secretase inhibitor (DAPT) inhibited IL-6 secretion of RA FLSs in response to TNF-α while treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-α stimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.
21884469 Effect of various anticoagulant agents on large-volume leukocytapheresis using new Cellsor 2011 Aug We conducted a study to evaluate the effect of various anticoagulant agents on large-volume leukocytapheresis using the new Cellsorba CS-180S Filter filled with a changed solution of sodium pyrosulfite and sodium carbonate. We conducted the study on a total of 12 cases of rheumatoid arthritis. As the anticoagulant agents we used sodium citrate, nafamostat mesilate and low molecular weight heparin. The new Cellsorba CS-180S was safely used with the various blood anticoagulant agents. Also, through adjustment of the sodium citrate percentage to the blood flow volume, it is hypothesized that it is possible to increase the neutrophil removal rate.
21457565 Design of cohort studies in chronic diseases using routinely collected databases when a pr 2011 Apr 1 BACKGROUND: There has been little research on design of studies based on routinely collected data when the clinical endpoint of interest is not recorded, but can be inferred from a prescription. This often happens when exploring the effect of a drug on chronic diseases. Using the LifeLink claims database in studying the possible anti-inflammatory effects of statins in rheumatoid arthritis (RA), oral steroids (OS) were treated as surrogate of inflammatory flare-ups. We compared two cohort study designs, the first using time to event outcomes and the second using quantitative amount of the surrogate. METHODS: RA patients were extracted from the LifeLink database. In the first study, patients were split into two sub-cohorts based on whether they were using OS within a specified time window of the RA index date (first record of RA). Using Cox models we evaluated the association between time-varying exposure to statins and (i) initiation of OS therapy in the non-users of OS at RA index date and (ii) cessation of OS therapy in the users of OS at RA index date. In the second study, we matched new statin users to non users on age and sex. Zero inflated negative binomial models were used to contrast the number of days' prescriptions of OS in the year following date of statin initiation for the two exposure groups. RESULTS: In the unmatched study, the statin exposure hazard ratio (HR) of initiating OS in the 31451 non-users of OS at RA index date was 0.96(95% CI 0.9,1.1) and the statin exposure HR of cessation of OS therapy in the 6026 users of OS therapy at RA index date was 0.95 (0.87,1.05). In the matched cohort of 6288 RA patients the statin exposure rate ratio for duration on OS therapy was 0.88(0.76,1.02). There was digit preference for outcomes in multiples of 7 and 30 days. CONCLUSIONS: The 'time to event' study design was preferable because it better exploits information on all available patients and provides a degree of robustness toward confounding. We found no convincing evidence that statins reduce inflammation in RA patients.
22983539 Association of AFF1 rs340630 and AFF3 rs10865035 polymorphisms with systemic lupus erythem 2012 Dec The aim of this study was to evaluate whether two single-nucleotide polymorphisms (SNPs), AF4/FMR2 family, member 1 (AFF1) rs340630 and AF4/FMR2 family, member 3 (AFF3) rs10865035, show significant evidence for association with systemic lupus erythematosus (SLE) in a Chinese population. A total of 868 Chinese patients with SLE and 975 geographically and ethnically matched healthy control subjects were enrolled in the current study. The genotypes of these two SNPs were determined by Sequenom MassArray technology. Significant evidence for association of AFF3 rs10865035 with SLE was detected (for A versus G, P = 4.81 × 10(-4), odds ratio (OR) 1.26, 95% confidence interval (95% CI) 1.11-1.44). However, no association between AFF1 rs340630 and SLE was found in the Chinese population (for A versus G, P = 0.79, OR 0.98, 95% CI 0.86-1.12). No significant evidence for association of AFF3 rs10865035 polymorphism with any clinical features was detected. By targeting a variant with convincing evidence for association with rheumatoid arthritis, significant association of AFF3 rs10865035 with SLE was detected in the Chinese population, indicating that AFF3 might be a common autoimmunity gene. Further case-control studies based on larger sample sizes in diverse ethnic populations are required to clarify the role of AFF1 rs340630 in SLE.
22911528 Body composition and serum levels of adiponectin, vascular endothelial growth factor, and 2012 Aug AIM: To investigate differences in body composition and body mass index (BMI) in patients with rheumatoid arthritis (RA) and their correlations with serum production of adiponectin, interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). METHODS: The study included 83 patients (age 53±5 years) with RA treated with methotrexate. We determined their BMI, fat mass, and fat-free mass using bioimpedance analysis, and serum concentrations of adiponectin, VEGF, and IL-6 using immunoassay analysis. RESULTS: Normal BMI was found in 39 (47%), overweight and obesity in 26 (31%), and underweight in 18 (22%) patients. Concentration of adiponectin was lower in overweight/obese patients than in patients with normal BMI (2.1 [0.8-3.9] μg/mL vs 8.9 (7.2-11.3) μg/mL). In underweight patients, it was moderately increased (12.7 [9.3-14.8] μg/mL) and the correlation between the concentrations of adiponectin and IL-6 was positive (r=0.4; P=0.01). Concentrations of VEGF and IL-6 were increased in all groups with RA. The overweight/obese group showed a negative correlation between the concentrations of adiponectin and VEGF (r=- 0.34; P=0.04), a positive correlation between VEGF concentration and fat mass (r=0.39; P=0.02), and a negative correlation between adiponectin concentration and fat mass (r=- 0.23; P=0.02). CONCLUSION: Inflammatory and angiogenesis activation was found in RA patients with all types of body composition, but only in those with obesity and overweight there was a direct antagonism between adiponectin and VEGF. Further research is needed to identify possible regimens of metabolic correction in different variations of body composition.
21782923 Risk factors of gastrointestinal and hepatic adverse drug reactions in the treatment of rh 2012 Jun 1 ETHNOPHARMACOLOGICAL RELEVANCE: The exploration of risk factors on the gastrointestinal adverse drug reactions (GI ADRs) and hepatic ADRs in the treatment of rheumatoid arthritis (RA) with traditional Chinese medicien (CM) and convertional Western Medicien (WM) therapy will benifit the clincial drug administration. METHODS: A multi-center, randomized-clinical trial was conducted on RA patients in China. After 12 and 24 weeks of treatment, the efficacy and safety of WM therapy and CM therapy were evaluated. The Chi-square and logistic regression were conducted to analyze the correlations between the biological parameters, CM symptoms and the ADRs. RESULTS: 505 patients were recruited from 9 centers and randomly assigned into WM therapy group (n=251) or CM group (n=254). 397 of them completed the 24 week treatment (194 in WM and 203 in CM group). Total ADRs incidence and withdrawal rates were similar in two groups. For the patients treated with WM, logistic regression analysis showed that CRP level was negatively related to GI ADRs (p<0.05), dizziness was positively related to GI ADRs (p<0.05); and IgG level and chills were positively related to hepatic ADRs (p<0.01, p<0.05). In the patients treated with CM, no laboratory measurements were found related with GI ADRs and hepatic ADRs, lassitude and nocturia were risk factors for GI ADRs, cold extremities for hepatic ADRs, respectively (p<0.05). CONCLUSION: CRP in normal scale and dizziness were the risk factors for GI ADRs, higher IgG level and chills were the risk factors for hepatic ADRs in the RA patients treated with conventional WM therapy. Lassitude and nocturia were the risk factors for GI ADRs, and cold extremities were the risk factors for hepatic ADRs in the RA patients treated with CM therapy.
23212593 JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. 2013 May Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ production and proliferation of CD4(+) T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.
22207197 Reduction in sickness absence in patients with rheumatoid arthritis receiving adalimumab: 2012 Dec The aim of this noninterventional study (NIS) was to analyze the changes in sickness absence, disease activity, and functional capacity in employed rheumatoid arthritis (RA) patients during adalimumab treatment. RA patients receiving adalimumab according to label instructions (40 mg every other week) were evaluated at regular intervals in a multicenter prospective NIS. Patients provided information on sickness absence in the 12 months preceding treatment initiation (baseline) and at months 6 and 12. Disease activity was assessed by the Disease Activity Score using 28 joints, and physical function was assessed via the Hannover Functional Ability Questionnaire, a patient self-questionnaire comparable with the Health Assessment Questionnaire-Disability Index. We present data on 1,157 patients who were employed (part time or full time) at baseline. Patients were categorized by the length of sickness absence at baseline. At baseline, patients with absences of 6 weeks or more in the previous year (n = 226 [19.5%]) accounted for 77% of the documented weeks of sickness absence, and patients with absences of more than 12 weeks (n = 98 [8.5%]) accounted for 54% of sickness absence weeks. During 12 months of adalimumab treatment, disease activity decreased, functional capacity improved, and sickness absence was reduced. The greatest decrease in sickness absence was observed in patients with more than 12 weeks of sick leave in the year prior to adalimumab therapy. These patients also showed gains in function comparable with those observed in other employed patients. We conclude that sustaining and improving functional capacity represent the key to preservation of work capability.
21241497 Perceived barriers to integrated care in rheumatoid arthritis: views of recipients and pro 2011 Jan 17 BACKGROUND: A number of recent reports published in the UK have put the quality of care of adults with Rheumatoid Arthritis (RA) centre stage. These documents set high standards for health care professionals and commissioning bodies that need to be implemented into routine clinical practice. We therefore have obtained the views of recipients and providers of care in inner city settings as to what they perceive are the barriers to providing integrated care. METHODS: We conducted focus groups and face to face interviews between 2005-8 with 79 participants (patients, carers, specialist medical and nursing outpatient staff and general practitioners (GPs)) working in or attending three hospitals and three primary care trusts (PCT). RESULTS: Three barriers were identified that stood in the way of seamless integrated care in RA from the perspective of patients, carers, specialists and GPs: (i) early referral (e.g. 'gate keeper's role of GPs); (ii) limitations of ongoing care for established RA (e.g. lack of consultation time in secondary care) and (iii) management of acute flares (e.g. pressure on overbooked clinics). CONCLUSION: This timely study of the multi-perspective views of recipients and providers of care was conducted during the time of publications of many important reports in the United Kingdom (UK) that highlighted key components in the provision of high quality care for adults with RA. To achieve seamless care across primary and secondary care requires organisational changes, greater personal and professional collaboration and GP education about RA.
22018199 Long-term prednisone in doses of less than 5 mg/day for treatment of rheumatoid arthritis: 2011 Sep This article summarises the experience of one academic rheumatologist in treatment of patients with rheumatoid arthritis (RA) over 25 years from 1980-2004 with low-dose prednisone, most with <5 mg/day over long periods. A database was available which included medications and multidimensional health assessment questionnaire (MDHAQ) scores for physical function, pain, and routine assessment of patient index data (RAPID3), completed by all patients at all visits in the infrastructure of care. Most patients were treated with long-term low-dose prednisone, often from the initial visit and indefinitely, and with methotrexate after 1990. The mean initial prednisone dose declined from 10.3 mg/day in 1980-1984 to 3.6 mg/day in 2000-2004. Although no formal criteria were used to determine the initial dose, prednisone doses were higher in patients who had more severe MDHAQ/RAPID3 scores, as expected, reflecting confounding by indication. Similar improvements were seen in clinical status over 12 months in patients treated with <5 vs. ≥ 5 mg/day prednisone, and maintained for >8 years. Adverse effects were primarily bruising and skin-thinning, with low levels of hypertension, diabetes, and cataracts, although this information was based only on self-report rather than systematic assessment by a health professional. These data reflect limitations of observational data. However, a consecutive patient database may provide long-term information not available from clinical trials. The data document that prednisone at doses <5 mg/day over long periods appears acceptable and effective for many patients with RA at this time. Further clinical trials and long-term observational studies are needed to develop optimal treatment strategies for patients with RA with low-dose prednisone.
22770979 Presence of multiple independent effects in risk loci of common complex human diseases. 2012 Jul 13 Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases.
22523223 Screening for IgG antinuclear autoantibodies by HEp-2 indirect fluorescent antibody assays 2012 May We evaluated 5 commercially available HEp-2 antinuclear antibody (ANA) indirect fluorescent antibody (IFA) assays using patient serum samples from 45 patients with rheumatoid arthritis, 50 with systemic lupus erythematosus (SLE), 35 with scleroderma, 20 with Sjögren syndrome, 10 with polymyositis, and 100 healthy control subjects. In addition, 12 defined serum samples from the Centers for Disease Control and Prevention and 100 patient serum samples sent to ARUP Laboratories (Salt Lake City, UT) for ANA IFA testing were also examined (n = 372). Standardization among the HEp-2 IFA assays occurred when they exhibited the same titer ± 1 doubling dilution. Agreement of the 5 assays was 78%. Within the specific groups of serum samples, agreement ranged from 44% in scleroderma serum samples to 93% in healthy control subjects, with 72% agreement in the SLE group. Variations in slide and substrate quality were also noted (ie, clarity, consistency of fluorescence, cell size, number and quality of mitotic cells). Along with subjectivity of interpretation, HEp-2 IFA assays are also vulnerable to standardization issues similar to other methods for ANA screening.
22634718 Liver X receptor regulates rheumatoid arthritis fibroblast-like synoviocyte invasiveness, 2012 Sep 7 Fibroblast-like synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA), yet little is known about its regulation. In this study we aimed to determine the role of the nuclear receptor liver X receptor (LXR) in FLS invasion. FLS were isolated from synovial tissues obtained from RA patients and from DA rats with pristane-induced arthritis. Invasion was tested on Matrigel-coated chambers in the presence of the LXR agonist T0901317, or control vehicle. FLS were cultured in the presence or absence of T0901317, and supernatants were used to quantify matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, interleukin-6 (IL-6), tumor necrosis factor-α and C-X-C motif chemokine ligand 10 (CXCL10). Nuclear factor-κB (NF-κB) (p65) and Akt activation, actin cytoskeleton, cell morphology and lamellipodia formation were also determined. The LXR agonist T0901317 significantly reduced DA FLS invasion by 99% (P ≤ 0.001), and RA FLS invasion by 96% (P ≤ 0.001), compared with control. T0901317-induced suppression of invasion was associated with reduced production of activated MMP-2, IL-6 and CXCL10 by RA FLS, and with reduction of actin filament reorganization and reduced polarized formation of lamellipodia. T0901317 also prevented both IL-1β-induced and IL-6-induced FLS invasion. NF-κB (p65) and Akt activation were not significantly affected by T0901317. This is the first description of a role for LXR in the regulation of FLS invasion and in processes and pathways implicated both in invasion as well as in inflammatory responses. These findings provide a new rationale for considering LXR agonists as therapeutic agents aimed at reducing both inflammation and FLS-mediated invasion and destruction in RA.
21765110 Natural killer-22 cells in the synovial fluid of patients with rheumatoid arthritis are an 2011 Oct OBJECTIVE: To determine the role of natural killer (NK)-22 cells in the pathogenesis of rheumatoid arthritis (RA). METHODS: Using flow cytometry, the proportions of NK-22 cells and intracellular contents of perforin, granzyme B, and interferon-γ (IFN-γ) were determined in the peripheral blood (PB) and synovial fluid (SF) of patients with RA and healthy individuals. The levels of interleukin 22 (IL-22) and tumor necrosis factor-α (TNF-α) in the NK-22 supernatant and gene expressions were measured using ELISA and QuantiGene Plex assay, respectively. The effect of NK-22 supernatant on the proliferation of fibroblast-like synoviocytes (FLS) and recombinant human IL-22 (rhIL-22) on the production of monocyte chemoattractant protein 1 (MCP-1) by RA FLS was detected using the yellow tetrazolium salt method and ELISA, respectively. The relationship between the proportions of NK-22 cells and disease activity was analyzed. RESULTS: NKp44 and CCR6 were expressed in a larger population of SF NK cells than in the PB NK cells of patients with RA. NK-22 cells produce low content of perforin, granzyme B, and IFN-γ. NK-22 cells in vitro can secrete IL-22 and TNF-α and there was increased messenger RNA coding for IL-22 and TNF-α. NK-22 supernatant can induce the proliferation of RA FLS. Addition of IL-22 antibody plus TNF-α antibody inhibited the proliferation of FLS induced by the NK-22 supernatant. Both rhIL-22 1 ng/ml and rhIL-22 10 ng/ml induced the production of MCP-1 by RA FLS. The NK-22 proportions were positively correlated with disease activity. CONCLUSION: NK-22 cells are increased in patients with RA and might play a role in the pathogenesis of RA through the production of IL-22 and TNF-α. The proportion of NK-22 cells and disease activity were highly correlated.
22684431 Phase II dose-response study of abatacept in Japanese patients with active rheumatoid arth 2013 Mar OBJECTIVE: The objective of this study was to assess the response to abatacept at doses of 2 mg/kg and 10 mg/kg compared to placebo in patients with active rheumatoid arthritis (RA) with an inadequate clinical response to methotrexate (MTX). METHODS: In this multicenter, placebo-controlled, double-blind, parallel-group, dose-response study, 195 Japanese patients with active RA with an inadequate response to MTX were randomized 1:1:1 to receive 10 mg/kg or 2 mg/kg abatacept plus MTX, or placebo plus MTX, for 24 weeks. RESULTS: Abatacept demonstrated a dose-response relationship when given at 2 and 10 mg/kg. Based on the American College of Rheumatology criteria (20, 50, and 70 %), the responses to 10 mg/kg abatacept were significantly greater than those to placebo at week 24 (p < 0.001). Smaller yet statistically significant responses were also seen in the 2 mg/kg abatacept group. Overall rates of adverse events, serious adverse events, and treatment discontinuations because of adverse events were comparable in all three groups. CONCLUSIONS: Abatacept (2 mg/kg and 10 mg/kg) showed a dose-response relationship in Japanese patients with active RA with an inadequate clinical response to MTX. Administration of abatacept in combination with MTX for 24 weeks was well tolerated.
22047626 Oral ezatiostat HCl (Telintra®, TLK199) and idiopathic chronic neutropenia (ICN): a case 2011 Nov 2 Idiopathic chronic neutropenia (ICN) describes a heterogeneous group of hematologic diseases characterized by low circulating neutrophil levels often associated with recurrent fevers, chronic mucosal inflammation, and severe systemic infections. The severity and risk of complications, including serious infections, are inversely proportional to the absolute neutrophil count (ANC), with the greatest problems occurring in patients with an ANC of less than 0.5 × 109/L. This case report describes a 64-year-old female with longstanding rheumatoid arthritis who subsequently developed ICN with frequent episodes of sepsis requiring hospitalization and prolonged courses of antibiotics over a 4-year period. She was treated with granulocyte colony stimulating factors (G-CSF) but had a delayed, highly variable, and volatile response. She was enrolled in a clinical trial evaluating the oral investigational agent ezatiostat. Ezatiostat, a glutathione S-transferase P1-1 inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitor stem cells. She responded by the end of the first month of treatment with stabilization of her ANC (despite tapering and then stopping G-CSF), clearing of fever, and healing of areas of infection. This ANC response to ezatiostat treatment has now been sustained for over 8 months and continues. These results suggest potential roles for ezatiostat in the treatment of patients with ICN who are not responsive to G-CSF, as an oral therapy alternative, or as an adjunct to G-CSF, and further studies are warranted.
22656072 Summary of AHRQ's comparative effectiveness review of drug therapy for rheumatoid arthriti 2012 May BACKGROUND: In 2011, the Agency for Health Care Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of disease-modifying anti-rheumatic drugs (DMARDs) used to treat adults with rheumatoid arthritis (RA). The publication was an update to a 2007 report. A total of 258 published articles were used in the AHRQ review to compare the effectiveness of corticosteroids, and oral and biologic DMARDs in the treatment of RA. Head-to-head studies and prospective cohort trials were used to compare one drug to another in determining efficacy and effectiveness. AHRQ compiled this report in an attempt to summarize and integrate the available data for clinicians to make evidence based practice decisions for their patients since there is limited consensus among the medical community regarding the comparative effectiveness of drugs used to treat RA. The report reveals there is still much research to be done concerning the side effects of these agents and their influence in different patient subgroups. OBJECTIVES: To: (a) utilize review findings to make diagnostic and treatment management decisions in clinical practice, (b) inform clinicians on the findings from the updated AHRQ's 2011 comparative effectiveness review on drug therapy for RA in adults, and (c) identify shortcomings in the current research and future directions revealed by the report. SUMMARY: Rheumatoid arthritis is a major public health burden. The 2011 updated AHRQ report includes several new medications approved by the FDA since 2007. The review includes 31 head-to-head randomized clinical trials (RCTs), 1 head-to-head nonrandomized controlled trial, 44 placebo controlled trials, 28 meta-analyses or systematic reviews, and 107 observational studies. Most of the studies used for the comparative analysis are of fair quality with an insufficient to moderate strength of evidence assigned to the findings (Table 1). A mixed treatment comparisons (MTC)meta-analysis from the AHRQ report found that the biologic etanercept has a higher probability of improvement in disease activity compared with other biologic DMARDs, but the MTC findings have a low strength of evidence and caution is recommended in the interpretation of this weak evidence. For patients with early RA, limited evidence precludes conclusions about the superiority of one combination therapy versus another. The data are also inconclusive for comparisons of therapeutic similarity among oral DMARDs including the limitation created by differences inmethotrexate (MTX) dosing across trials. Extensive clinical experience over the years support the preferred use of MTX in most patients versus other oral DMARDs as well as its use in multidrug regimens, whereas there is little data on the use of oral DMARDs in combination with biologic agents. The review does not support a specific biologic DMARD over another due to the lack of head-to-head trials comparing these agents using validated RA outcome measures. The data show that the majority of biologics have approximately the same efficacy except for anakinra, which was found to be less effective. The biologic and oral DMARDs are similar in overall tolerability, but several studies suggest that adverse events are more common with biologic DMARDs versus oral DMARDs. Based on limited evidence, the oral DMARDs do not appear to have an increased risk of severe adverse events including cardiovascular events and cancer. Although most studies also found no increased risk of cardiovascular events or cancer with the biologic DMARDs, cohort studies show an increased risk of heart failure with adalimumab, etanercept, and infliximab compared with oral DMARDs. The updated AHRQ review synthesizes the current literature on therapies used for the treatment of RA in adults. The investigators are also able to identify pertinent research gaps in the literature that can be addressed with future research.
23176083 Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the DREA 2012 Nov 23 INTRODUCTION: Clinical trials have demonstrated that treatment-to-target (T2T) is effective in achieving remission in early rheumatoid arthritis (RA). However, the concept of T2T has not been fully implemented yet and the question is whether a T2T strategy is feasible in daily clinical practice. The objective of the study was to evaluate the adherence to a T2T strategy aiming at remission (Disease Activity Score in 28 joints (DAS28) < 2.6) in early RA in daily practice. The recommendations regarding T2T included regular assessment of the DAS28 and advice regarding DAS28-driven treatment adjustments. METHODS: A medical chart review was performed among a random sample of 100 RA patients of the DREAM remission induction cohort. At all scheduled visits, it was determined whether the clinical decisions were compliant to the T2T recommendations. RESULTS: The 100 patients contributed to a total of 1,115 visits. The DAS28 was available in 97.9% (1,092/1,115) of the visits, of which the DAS28 was assessed at a frequency of at least every three months in 88.3% (964/1,092). Adherence to the treatment advice was observed in 69.3% (757/1,092) of the visits. In case of non-adherence when remission was present (19.5%, 108/553), most frequently medication was tapered off or discontinued when it should have been continued (7.2%, 40/553) or treatment was continued when it should have been tapered off or discontinued (6.2%, 34/553). In case of non-adherence when remission was absent (42.1%, 227/539), most frequently medication was not intensified when an intensification step should have been taken (34.9%, 188/539). The main reason for non-adherence was discordance between disease activity status according to the rheumatologist and DAS28. CONCLUSIONS: The recommendations regarding T2T were successfully implemented and high adherence was observed. This demonstrates that a T2T strategy is feasible in RA in daily clinical practice.