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ID PMID Title PublicationDate abstract
19779026 Association of myocardial infarctions with COX-2 inhibition may be related to immunomodula 2010 May Cyclooxygenase (COX) inhibitors remain a major class of drugs in rheumatology and their widespread use is expected to continue. The view that a prothrombotic effect explains the increase in myocardial infarction (MI) associated with both COX-2 selective and traditional NSAIDs (tNSAIDs) has been increasingly questioned. We review the evidence that prostanoids direct the immune response away from a Th1 response and that consequently inhibition of prostaglandin synthesis results in augmentation of the Th1 response by limiting prostanoid synthesis. Although the role of prostanoids as mediators of inflammation in the periphery is well understood, the systemic immunomodulatory role of prostanoids shifting the immune response away from a Th1 type is less appreciated. Atherosclerosis is an inflammatory arterial disease driven by a Th1 type immune response. Moreover, the vulnerable phenotype of atheroma is associated with the cellular Th1 immune response in contrast to the stable plaque phenotype associated with a Th2 type response. We propose a class effect of COX-2 selective and tNSAIDs, which results in augmentation of Th1-mediated atherogenesis/ production of pro-atherogenic cytokines associated with detrimental plaque remodeling, instability, rupture and embolization resulting in MI. Understanding of the Th1 mediated immunity, which underlies the cardiovascular, and the non-Th1, which underlies gastrointestinal adverse effects associated with the use of COX inhibitors, should lead to better risk assessment and the development of anti-inflammatory treatments with improved safety. Our explanation also emphasizes the pharmacological effects and consequences of immunomodulation in the inflammation associated with atherosclerosis and other Th1- as well as non-Th1-driven diseases.
19654217 Validity of physician-reported hospitalized infections in a US arthritis registry. 2009 Oct OBJECTIVE: In safety studies, events reported as infections may be misclassified and, therefore, affect the validity of estimated risks associated with biologic agents. Using data from the Consortium of Rheumatology Researchers of North America (CORRONA), we evaluated hospitalized infection reports contributed by rheumatologists to establish their validity. METHODS: All patients hospitalized with infections from 2002 to 2007 reported to CORRONA were examined and compared with information from hospital discharge summaries and other confirmatory data. Infectious episodes were classified by two physicians as confirmed, empirically treated, possible or unlikely. RESULTS: Of 562 reported hospitalized infectious episodes, 9% were classified as unlikely and had minimal or no supporting evidence for infection, leaving 509 hospitalized infectious episodes. Of these, 53% of the infectious episodes were classified as confirmed, 15% empirically treated and 32% possible. The confirmation status of infectious episodes for younger or biologic-exposed participants was similar to older and biologic-unexposed participants. CONCLUSION: More than two-thirds of hospitalized infections reported by rheumatologists were confirmed or had evidence that the physician was treating an infection. In almost all cases, there was at least modest evidence for an infection. Future studies should consider case definitions for infections or sensitivity analyses, or both, regarding the certainty of an infection to account for possible misclassification and reduce bias.
21298696 Risk factors for lower extremity fatigue among assembly plant workers. 2011 Mar BACKGROUND: Work-related fatigue of the lower extremities is a known cause of lost productivity and significant employer costs. Common workplace solutions to reduce fatigue levels include anti-fatigue matting, shoe orthoses, or sit/stand work stations. However, assessment of these anti-fatigue measures within the workplace has been limited. METHODS: This was a cross sectional study in an automotive assembly plant on employees with at least 6 months tenure. Subject data were collected via questionnaires including Likert-scale questions to define fatigue severity. Jobs were evaluated for lower extremity ergonomic exposures via videotaping, pedometers, interviews, and industrial engineering records. RESULTS: Lower extremity fatigue at the end of the work day was associated with a higher prevalence of smoking, rheumatoid arthritis, job dissatisfaction, use of shoes with firmer outsoles, and increased time on the job spent standing or walking. Supervisor support and increased time spent on carpet were protective. Lower extremity fatigue that interfered with activities outside of work had additional risk factors including higher BMI, prior diagnosis of osteoarthritis, and increased hours per week spent working. CONCLUSIONS: While these results identify carpet as being protective against lower extremity fatigue, no similar relationship was identified for anti-fatigue mats. No adverse relationship was found between hard surfaces such as concrete and lower extremity fatigue. Given the high costs associated with work-related fatigue, future areas for potential intervention include smoking cessation, specific shoe recommendations, and enhancing psychosocial aspects of work such as supervisor support.
20956186 Organising pneumonia can be the inaugural manifestation in connective tissue diseases, inc 2010 Jun Connective tissue diseases are known to be one of the causes of organising pneumonia (OP). However, this association is rare and signs of OP usually occur in the context of an already diagnosed disease. We report three cases of OP preceding the articular symptoms of the underlying connective tissue disease by 3-6 months in two cases of rheumatoid arthritis and by 36 months in one patient with primary Sjögren's syndrome. The diagnosis of post-infectious OP had initially been suspected in the three cases and the patients had not been followed up further. The occurrence of OP preceding articular or any other extrapulmonary involvement of connective tissue disease had been reported in only four cases in the literature and, to our knowledge, no case preceding Sjögren's syndrome had ever been reported. These observations suggest that exhaustive investigations should be considered when OP is diagnosed, including antinuclear auto-antibodies and investigations for Sjögren's syndrome, even when there are no clinical signs suggesting an underlying connective tissue disease. These investigations should also be repeated during the course of the disease, especially in the case of OP continuing to progress under treatment and, of course, if signs of connective tissue disease appear.
19821440 Biologics for rheumatoid arthritis: an overview of Cochrane reviews. 2009 Oct 7 BACKGROUND: The biologic disease-modifying anti-rheumatic drugs (DMARDs) are very effective in treating rheumatoid arthritis (RA), however there is a lack of head-to-head comparison studies. OBJECTIVES: To compare the efficacy and safety of abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab in patients with RA. METHODS: This 'Overview of Reviews' was done by including all Cochrane Reviews on Biologics for RA available in The Cochrane Library. We included only data on standard dosing regimens for these biologic DMARDs from placebo-controlled trials. The primary efficacy and safety outcomes were ACR50 and withdrawals due to adverse events. We calculated Risk Ratios (RR) for efficacy, Odds Ratio (OR) for safety and combined estimates of events across the placebo groups as the expected Control Event Rate (CER). Indirect comparisons of biologics were performed for efficacy and safety using a hierarchical linear mixed model incorporating the most important study-level characteristic (i.e. type of biologic) as a fixed factor and study as a random factor; reducing the between study heterogeneity by adjusting for the interaction between the proportion of patients responding on placebo and the duration of the trial. MAIN RESULTS: From the six available Cochrane reviews, we obtained data from seven studies on abatacept, eight on adalimumab, five on anakinra, four on etanercept, four on infliximab, and three on rituximab.The indirect comparison estimates showed similar efficacy for the primary efficacy outcome for all biologics with three exceptions. Anakinra was less efficacious than etanercept with a ratio of RRs (95% CI; P value) of 0.44 (0.23 to 0.85; P = 0.014); anakinra was less efficacious than rituximab, 0.45 (0.22 to 0.90; P = 0.023); and likewise adalimumab was more efficacious than anakinra, 2.34 (1.32 to 4.13; P = 0.003).In terms of safety, adalimumab was more likely to lead to withdrawals compared to etanercept, with a ratio of ORs of 1.89 (1.18 to 3.04; P = 0.009); anakinra more likely than etanercept, 2.05 (1.27 to 3.29; P = 0.003); and likewise etanercept less likely than infliximab, 0.37 (0.19 to 0.70; P = 0.002). AUTHORS' CONCLUSIONS: Based upon indirect comparisons, anakinra seemed less efficacious than etanercept, adalimumab and rituximab and etanercept seemed to cause fewer withdrawals due to adverse events than adalimumab, anakinra and infliximab. Significant heterogeneity in characteristics of trial populations imply that these finding must be interpreted with caution. These findings can inform physicians and patients regarding their choice of biologic for treatment of RA.
20554957 Wnt5a induces endothelial inflammation via beta-catenin-independent signaling. 2010 Jul 15 Wnt signaling has been implicated in certain inflammatory diseases. However, the biological role in the inflammatory regulation remains to be characterized. We investigated the regulation by Wnt signaling in endothelial cells, which are active participants and regulators of inflammation. Wnt5a induces cyclooxygenase-2 expression and enhances inflammatory cytokines rapidly, whereas Wnt3a shows limited effects, suggesting a role for beta-catenin-independent Wnt signaling in the inflammatory endothelial activation. Pulse-like treatment of Wnt5a induces cyclooxygenase-2 more efficiently than continuous treatment. Wnt5a and TNF-alpha regulate subsets of cytokines overlapping, only partially, with each other. Calcium ionophore enhances endothelial inflammation similarly, whereas calcium chelators and protein kinase C inhibitor block Wnt5a-induced activation, suggesting a role for the Wnt/Ca(2+)/protein kinase C pathway in endothelial inflammatory regulation. Wnt5a activates RelA nuclear translocation and DNA binding. Activated blood vessels, histiocytes, and synoviocytes express Wnt5a in atherosclerosis and rheumatoid arthritis but not in normal tissue, supporting the role of Wnt5a as an inflammatory mediator in vivo. Our data suggest that endothelial inflammation is regulated by a dual system consisting of beta-catenin-independent Wnt signaling and TNF-alpha-mediated signaling.
20460737 C2-ceramide inhibits the prostaglandin E2-induced accumulation of cAMP in human gingival f 2010 Apr Ceramide is generated by the hydrolysis of membrane sphingomyelin by sphingomyelinase and is implicated in multiple signaling pathways, including those regulating differentiation, inflammation and immune responses. Excess formation of prostaglandin E(2) (PGE(2)) is thought to increase susceptibility to infection, rheumatoid arthritis and inflammation, including periodontal diseases. We investigated the inhibitory effect of C(2)-ceramide, a short-chain ceramide analog, on the PGE(2)-stimulated accumulation of cAMP in human gingival fibroblasts. In human gingival fibroblasts pre-treated with C(2)-ceramide for 18 h, the PGE(2)-stimulated accumulation of cAMP was reduced, but an inactive C(2)-ceramide analog had no such effect. The accumulation of cAMP induced by EP2 and EP4 receptor agonists (ONO-AE1-259 and ONO-AE1-329, respectively) was inhibited in cells treated with C(2)-ceramide. However, treatment with C(2)-ceramide had no effect on the expression of mRNAs encoding the EP2 and EP4 receptors. Accumulation of cAMP could be induced by cAMP-elevating agents (forskolin, isobutylmethylxanthine and mastparan) but was not reduced by treatment with C(2)-ceramide. These observations suggest that C(2)-ceramide attenuates PGE(2) receptor function and consequently inhibits the accumulation of cAMP in human gingival fibroblasts.
19399534 Relevance of the cranioaxial angle in the occipitocervical stabilization using an original 2009 Jun We present a retrospective study on a series composed of 50 patients, treated between 1992 and 2006, affected by pathologies of the craniocervical junction. All the patients were treated using an innovative procedure based on a cranial claw made up of low profile hooks, conceived by one of the authors. Advantages of this technique are, to our point of view, a higher resistance to cranial hooks dislodgment, when compared with screw fixation instrumentation, especially in pathological conditions, such as rheumatoid arthritis that leads to a qualitative deterioration of the bone stock and to the reduction of the occipital wall thickness. Occipitoaxial alignment was assessed radiographically using the McGregor line. We observed an improvement in the subjective evaluation of pain in all treated patients with a 46% improvement from the initial values. Moreover, patient stabilized with an occipitoaxial angle included in the physiological range showed better results either for the survival of the instrumentation or the onset of junctional pathology. Patients have been followed up afterwards and evaluated by the visual analogue scale for the assessment of pain and by the Nurick scale for the cases associated with myelopathy. We believe that cranial anchorage with a hook claw allows for an instrumentation provided with high stability, particularly useful in revision surgery and major instabilities. The study of the occipitoaxial angles showed that the better results and the long-lasting stability of the implant are correlated to a fusion angle included in the physiological range.
19861243 [Effect of soluble total proteins of Zaocys dumnades on interleukin-1beta, tumor necrosis 2009 Oct OBJECTIVE: To evaluate the effect of soluble total proteins of Zaocys dhumnades on the expressions of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and IL-10 in human fibroblast-like synoviocytes (FLS) cultured in vitro. METHODS: Primary cultured FLS isolated from the synovium of patients with rheumatoid arthritis (RA) were incubated in the presence of different concentrations (50, 150 and 450 microg/ml) of soluble total proteins of Zaocys dhumnades, with Tripterygium hypoglaucum Hutch (THH) and DMEM as the positive and negative controls, respectively. Enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to detect the expressions of IL-1beta, IL-10 and TNF-alpha in the FLS. RESULTS: The protein and mRNA levels of IL-1beta and TNF-alpha in the supernatant of the FLS exposed to 150 and 450 microg/ml of the soluble total proteins of Zaocys dhumnades decreased, while IL-10 protein and mRNA increased significantly as compared with those in the negative control group (P<0.01). CONCLUSION: The soluble total proteins of Zaocys dhumnades produce therapeutic effect on RA possibly by inhibiting IL-1beta and TNF-alpha and promoting IL-10 expressions in the FLS.
20609598 CXCL12 gene expression is upregulated by hypoxia and growth arrest but not by inflammatory 2011 Feb OBJECTIVES: CXCL12 is a constitutively expressed chemokine with important homeostatic functions. Increased CXCL12 expression has been observed in several inflammatory conditions, including rheumatoid arthritis (RA). This study was undertaken to identify potential mechanisms of regulation of CXCL12 gene expression by human fibroblasts under normal or inflammatory conditions. METHODS: Synovial fibroblasts (SF) were cultured from RA and osteoarthritis (OA) synovial tissues. CXCL12 mRNA expression was analysed by real time quantitative RT-PCR in RA-SF under different growth conditions, and exposed to hypoxia or to different pro-inflammatory factors. A 5'CXCL12 -1.4 kb promoter region fragment was cloned in a luciferase reporter plasmid and its activity analysed in human fibroblasts. RESULTS: CXCL12 mRNA expression was not constitutively increased in RA- compared to OA-SF. LPS, pro-inflammatory cytokines or growth factors did not induce CXCL12 mRNA expression in SF. Hypoxia and growth arrest by either serum starvation or confluent growth induced CXCL12 mRNA and protein expression in SF. Constitutive and induced expression of CXCL12 in fibroblasts was regulated at the transcriptional level by specific regions of the -1.4 kb promoter. CONCLUSIONS: Pro-inflammatory factors and cytokines do not up-regulate CXCL12 gene expression in SF. Growth arrest and hypoxia are potentially important inducers of CXCL12 expression in human fibroblasts and operate by regulating transcriptional activity of the promoter.
20137434 [Study on expressions of CD25 and CD127 in CD4+ peripheral T lymphocytes of patients with 2009 Sep 22 OBJECTIVE: To study the proportion of regulatory T cells (Tregs) in peripheral blood of patients with rheumatoid arthritis (RA) and investigate the significance of Tregs change in the incidence and inflammatory activity of RA. METHODS: Three-color fluorescence flow cytometry was used to detect the CD4, CD25 and CD127 markers in the peripheral blood lymphocytes of 25 RA patients and 31 healthy volunteers (HVs). The proportions of CD4(+)CD25(+), CD4(+)CD25(high), CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells were compared between the two groups and correlation analysis was conducted between Tregs and disease activity indices which including disease activity score (DAS28-4), tender joint count (TJC), swollen joint count (SJC), time of morning stiffness, patient's global assessment of disease activity on a 100 mm VAS by doctor and patients, erythrocyte sedimentation rate and C-reactive protein. RESULTS: The proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells in CD4(+) peripheral T lymphocytes were (2.53 +/- 0.85)% and (0.91 +/- 0.32)% respectively in RA group, while they were (3.22 +/- 0.97)% and (1.25 +/- 0.41)% in HV group. Both of the proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells were lower in RA group comparing with HV group, and both were significantly different between the two groups (P < 0.05). Correlation analysis indicated significant negative correlations of the proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells with DAS28-4 and TJC (P < 0.05), furthermore, CD4(+)CD25(high)CD127(-) T cells still showed significant negative correlation with the SJC and patient's global assessment of disease activity on a 100 mm VAS by patients (P < 0.05). CONCLUSION: The proportion of Tregs decreased in peripheral blood lymphocytes of patients with RA and the abnormality of Tregs may play an important role in the incidence and inflammatory activity of RA.
20974317 Subset analysis of patients experiencing clinical events of a potentially immunogenic natu 2010 Aug BACKGROUND: Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody directed against the interleukin-6 receptor. In Europe, TCZ is approved for use in combination with methotrexate in the treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have failed to respond to or were unable to tolerate previous therapy with one or more disease-modifying antirheumatic drugs or tumor necrosis factor (TNF) antagonists; in the United States, it is approved for the treatment of adult patients with moderate to severe active RA who have failed to respond to one or more TNF antagonists. As part of the Phase III clinical development program, the immunogenicity of TCZ was evaluated using a bridging ELISA; however, this assay is considered limited in detecting low-affinity or immunoglobulin G4 subisotype antidrug antibodies (ADAs). OBJECTIVE: This study assessed the validity of the ELISA for detecting anti-TCZ ADAs by using complementary bioanalytic assays to test samples from a subgroup of patients with clinical adverse events (AEs) of a potentially immunogenic nature, who were considered highly likely to have ADAs. The goal was to determine whether use of these additional assays led to detection of ADAs not found on the ELISA, thus minimizing the risk of false-negative results. METHODS: The Phase III program for TCZ consisted of 5 core studies in which adult patients with RA received either TCZ 4 or 8 mg/kg IV or control every 4 weeks, with or without concomitant antirheumatic therapy. Blood samples obtained at baseline and at regular intervals thereafter were tested using the ELISA for ADA screening and confirmation. Regardless of the results on ADA screening, samples from patients who developed clinical AEs of a potentially immunogenic nature (ie, falling within predefined system organ classes, occurring during or within 24 hours of TCZ infusion, considered related to TCZ therapy, or leading to study withdrawal) were subjected to additional testing with a surface plasmon resonance (SPR) assay for isotyping and epitope localization and a standard ImmunoCAP immunoglobulin E (IgE) assay made specific for TCZ. RESULTS: The 5 core studies and their open-label, longterm extension studies enrolled a total of 4199 adult patients with RA (82.1% female; 74.0% white; mean age, 52.0 years [range, 18-89 years]; mean weight, 73.4 kg [range, 35-150 kg]); 2928 patients received TCZ and 1271 received control. Of the 2816 samples from TCZ-treated patients tested, 64 (2.3%) had samples that tested positive at least once on the ELISA screening and confirmation assay, 48 (75.0%) of them at baseline. A clinical AE of a potentially immunogenic nature occurred during TCZ treatment in 21 patients, 8 of whom had an anaphylactic reaction. Eleven of the samples from these 21 patients had tested negative for AD As on the screening ELISA. Only 1 of these 11 patients tested positive for ADAs on both additional assays; all others tested negative. The results of the ELISA, SPR, and IgE assays were consistent for 16 of 18 tested patients (88.9%) who provided data on at least 2 of the 3 assays. CONCLUSIONS: Based on the findings of this analysis in a relevant patient population, the bridging-type screening and confirmation ELISA was a valid method of detecting anti-TCZ ADAs. Immunogenicity testing of samples from patients with clinical AEs of a potentially immunogenic nature using assays complementary to the ELISA added valuable information about the incidence and character of ADAs.
19940341 Mass spectrometric and peptide chip epitope mapping of rheumatoid arthritis autoantigen RA 2009 The protein termed RA33 was determined to be one major autoantigen in rheumatoid arthritis (RA) patients and antiRA33 auto-antibodies were found to appear shortly after onset of RA. They are often detectable before a final diagnosis can be made in the clinic. The aim of our study is to characterise the epitope of a monoclonal antiRA33 antibody on recombinant RA33 using mass spectrometric epitope mapping. Recombinant RA33 has been subjected to BrCN cleavage and fragments were separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Subsequent in-gel proteolytic digestion and mass spectrometric analysis determined the partial sequences in the protein bands. Western blotting of SDS-PAGE-separated protein fragments revealed immuno-positive, i.e. epitope-containing bands. BrCN-derived RA33 fragments were also separated by high- performance liquid chromatography (HPLC) and immuno-reactivity of peptides was measured by dot-blot analysis with the individual HPLC fractions after partial amino acid sequences were determined. The epitope region identified herewith was compared to data from peptide chip analysis with 15-meric synthetic peptides attached to a glass surface. Results from all three analyses consistently showed that the epitope of the monoclonal antiRA33 antibody is located in the aa79-84 region on recombinant RA33; the epitope sequence is MAARPHSIDGRVVEP. Sequence comparisons of the 15 best scoring peptides from the peptide chip analysis revealed that the epitope can be separated into two adjacent binding parts. The N-terminal binding parts comprise the amino acid residues "DGR", resembling the general physico-chemical properties "acidic/polar-small-basic". The C-terminal binding parts contain the amino acid residues "VVE", with the motif "hydrophobic-gap-acidic". The matching epitope region that emerged from our analysis on both the full-length protein and the 15-meric surface bound peptides suggests that peptide chips are indeed suitable tools for screening patterns of autoantibodies in patients suffering from autoimmune diseases.
19800850 Galectin-9 ameliorates immune complex-induced arthritis by regulating Fc gamma R expressio 2009 Dec Galectin-9 up-regulated Fc gamma RIIb expression of mouse peritoneal macrophages in vitro but down-regulated Fc gamma RIII expression. Galectin-9-treated macrophages stimulated with immune complexes (IC) produced less TNFalpha and IL-1 beta but more IL-10 than PBS-treated macrophages. Macrophage enhancing effects on IC-induced C5a and neutrophil chemotactic activity were also diminished for galectin-9-treated macrophages. In galectin-9-treated mice, the severity of IC-induced arthritis was reduced, as were pro-inflammatory cytokine levels in inflamed joints and serum C5a. Fc gamma RIIb expression of macrophages from galectin-9-treated mice was up-regulated, whereas Fc gamma RIII expression was down-regulated. Macrophages from galectin-9-treated mice produced less TNFalpha and IL-1 beta but more IL-10 than PBS-treated mice. Disease severity of galectin-9-transgenic mice was milder than wild-type mice, whereas that of galectin-9-deficient mice was exaggerated. Furthermore, macrophage Fc gamma RIIb expression in galectin-9-deficient mice was down-regulated, while Fc gamma RIII expression was up-regulated. These results suggest that galectin-9 suppresses IC-induced inflammation partly by regulating Fc gamma R expression on macrophages.
20501987 T cell large granular lymphocytic leukemia in association with Sjögren's syndrome. 2010 T cell large granular lymphocytic (LGL) leukemia is a rare condition accounting for 2-3% of all mature lymphoid leukemias. Here, we present the case of a 73-year-old woman presenting with neutropenia and anemia (hemoglobin 9.9 g/dl). Hematological assessment revealed the presence of a T cell LGL leukemia. At the time of T cell LGL leukemia diagnosis, the patient developed xerophthalmia and xerostomia, and a diagnosis of Sjögren's syndrome was made following salivary gland biopsy. The finding of large granular lymphocytes in the context of autoimmune disorders is well-known, though it often occurs with rheumatoid arthritis or in association with a positive autoantibody titer in the absence of an overt clinical picture. The concomitant presentation of T cell LGL leukemia with Sjögren's syndrome is a rare event which is worth reporting. Our patient was managed with immunosuppressive therapy and is still alive.
21081525 Generalisability of clinical registers used for drug safety and comparative effectiveness 2011 Mar OBJECTIVE: To determine coverage and generalisability of data in the Swedish Biologics Register ARTIS. METHODS: Patients with adult onset rheumatoid arthritis (RA) were identified in the National Patient Register and the Swedish Rheumatology Quality Register, including the ARTIS cohort of patients exposed to biological agents. Exposure to etanercept and adalimumab between 2006 and 2008 was determined by register linkage to the Prescribed Drug Register which contains patient-level data on >99% of all etanercept and adalimumab use in Sweden. RESULTS: Of 62 897 patients with RA, 6510 had received treatment with etanercept or adalimumab according to the Prescribed Drug Register. Of these, 5673 were also registered in ARTIS, resulting in a national coverage of 87%. The regional variation was small with >85% coverage in 18 of 21 counties. In multivariable analysis, ARTIS-registered and non-registered patients did not differ by age (p=0.62), sex (p=0.84) or education level (p=0.24). CONCLUSION: Nationwide drug dispensing and demographic data may function as quality metrics for coverage and generalisability assessments. Using such data, the coverage of ARTIS was estimated at 87% with no indications of compromised external generalisability regarding demography.
21163625 Bisphosphonate-related osteonecrosis of the jaws: a case series of 25 patients affected by 2011 Mar Bisphosphonates (BPs) are used to treat metabolic bone diseases, such as osteoporosis. In this study the occurrence of bisphosphonates-related osteonecrosis of the jaws (BRONJ) is reported in 25 patients who received BP therapy for osteoporosis with different drug schedules. From June 2005 to May 2009, 25 patients affected by BRONJ were observed. A history of oral surgery was reported for 18 patients (72%). Of the 22 patients treated by the authors, 20 (91%) recorded healing improvement with a mean follow-up of 16.6 months, with particular regard for those treated with oral surgery and laser applications (10/22, 45%) who were all characterised by complete mucosal healing over time. The risk of developing BRONJ in patients treated with BP for osteoporosis is lower than in cancer patients, but is not negligible. It is advisable for the prescribing physician to recommend a dental check-up prior to treatment, at least for patients who have not been to the dentist in the last 12 months. An early surgical and possible laser-assisted approach for patients who develop BRONJ is recommended.
18395421 Histologic characterization of human scarred vocal folds. 2009 Jul Vocal fold scarring remains a significant problem. Although several animal models have been developed to improve our understanding of the histopathology, the histologic features of scarred human vocal folds have rarely been reported. The present case studies aimed to define the histologic changes of scarred human vocal folds caused by cordectomy or cordotomy. Ten patients with the scarred vocal folds were involved in this study. Nine patients with early glottic cancer underwent endoscopic cordectomy, and one patient underwent superficial cordotomy for idiopathic scar. The postcordectomy or cordotomy scar was biopsied or resected 3-13 months after the original procedure. After confirming absence of any tumor in cancer patients, the remaining specimens were used in the present study. Histologic examination investigated deposition of extracellular matrix (ECM) including collagen, elastin, hyaluronic acid (HA), fibronectin, and decorin in the lamina propria of the scarred vocal folds. There was a wide range of variation in the deposition of ECM in scarred vocal folds. Excessive and disorganized collagen deposition was observed in most cases that had undergone deep resection of the lamina propria, whereas deposition of collagen was mild and well organized after superficial resection. Decorin was retained in all cases after superficial cordectomy or cordotomy, but varied after deep resection. Deposition of elastin, HA, and fibronectin varied regardless of depth of injury. Histology of scarred vocal folds may vary with degree of injury and individual healing mechanism.
20580412 Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical featu 2010 Dec OBJECTIVE: The induction or exacerbation of psoriasis in patients treated with tumor necrosis factor (TNF) antagonists is a well-established phenomenon. The goals of this comprehensive literature analysis were to update currently available data regarding this adverse event, to identify any clinical patterns in the cohort of reported patients, and to review the possible immunopathogenesis. METHODS: A systematic literature review was performed utilizing PubMed and Medline databases (1996 to August 2009) searching the index terms "tumor necrosis factor alpha inhibitor," "TNF," "infliximab," "etanercept," "adalimumab," combined with the terms "psoriasis," "pustular," "skin," "rash," "palmoplantar," and "paradoxical." All relevant articles were reviewed. Patients who did not appear to meet accepted classification criteria for their treated disease, who had a more probable explanation or other likely diagnosis for their skin findings or known possible triggering factor for the skin eruption, including infection, were excluded from this analysis. RESULTS: Two hundred seven cases met inclusion criteria for review. Of these, 43% were diagnosed with rheumatoid arthritis, 26% with seronegative spondyloarthropathy, and 20% with inflammatory bowel disease. Mean patient age was 45 years and 65% were female. Fifty-nine percent were being treated with infliximab, 22% with adalimumab, and 19% with etanercept. Lesion morphology included pustular psoriasis in 56%, plaque psoriasis in 50%, and guttate lesions in 12%; 15% experienced lesions of more than 1 type. No statistically significant predisposing factors for the development of new-onset psoriasis were found. Sixty-six percent of patients were able to continue TNF antagonist therapy with psoriasis treatments. The pathogenesis appears to involve disruption of the cytokine milieu with production of unopposed interferon-α production by plasmacytoid dendritic cells in genetically predisposed individuals. Genetic polymorphisms may play a role in this paradoxical reaction to TNF blockade. CONCLUSIONS: TNF antagonist induced psoriasis is a well-described adverse event without any known predisposing risk factors. Most patients can be managed conservatively without drug withdrawal. Registry data reporting is necessary to define the true incidence and prevalence of this condition. Genomic studies of affected patients may assist with identification of predisposed patients and elucidation of the molecular trigger of this perplexing response.
20471891 Whipple's disease diagnosed during biological treatment for joint disease. 2010 Jul OBJECTIVES: Increased susceptibility to infections is among the main safety concerns raised by biological agents. We describe five cases of Whipple's disease diagnosed during treatment with biological agents. METHODS: We retrospectively identified five cases of Whipple's disease diagnosed between 2003 and 2009 in patients treated with TNFalpha antagonists in five French hospitals. RESULTS: Five patients (four male; mean age: 50.4 years; range: 38-67) underwent biological therapy according to prior diagnoses of rheumatoid arthritis (n=2), ankylosing spondylitis (n=2), or spondyloarthropathy (n=1). Biological therapy failed to control the disease, which responded to appropriate antibiotics for Whipple's disease. Retrospectively, clinical symptoms before biological therapy were consistent with Whipple's disease. All five patients had favorable outcomes (mean follow-up, 29 months [13-71]). CONCLUSIONS: Biological therapy probably worsened preexisting Whipple's disease, triggering the visceral disorders. Whipple's disease must be ruled out in patients with joint disease, as patients with this spontaneously fatal condition should not receive immunosuppressive agents.