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ID PMID Title PublicationDate abstract
19703863 Rheumatoid synovial inflammation: pixel-by-pixel dynamic contrast-enhanced MR imaging time 2009 Oct PURPOSE: To analyze the distribution of different shapes of time-intensity curves (TICs) in synovial tissue of patients with rheumatoid arthritis (RA) and to compare relative numbers of TIC shapes between patients with RA and healthy control subjects. MATERIALS AND METHODS: This prospective study was approved by the institutional review board; patients and control subjects gave written informed consent. Dynamic contrast material-enhanced magnetic resonance (MR) imaging of the knee joint in five patients with early RA and in five control subjects was performed. Parametric maps showing seven TIC shape types were created. Spatial information of the synovial TIC shape distribution pattern and relative number of TIC shapes were calculated on a three-dimensional region of interest. Relative TIC shape numbers were compared by using a nonparametric Mann-Whitney U test. RESULTS: Synovial enhancement in patients with RA consisted of type 2 TIC shapes (slow enhancement) with heterogeneous zones of types 3 (fast enhancement followed by plateau phase), 4 (fast enhancement followed by early washout phase), and 5 (fast enhancement followed by slow enhancement increase) TIC shapes, compared with almost only type 2 TIC shapes in control subjects. The heterogeneous zones were seen in the lateral and medial knee compartments and around the cruciate ligaments. A significantly higher relative number of type 4 TIC shapes was observed in the patient group compared with the control group (16.5% vs 6.9%, P = .008). CONCLUSION: The pixel-by-pixel dynamic contrast-enhanced MR imaging TIC shape analysis may help distinguish patients with RA from control subjects on the basis of the relative number of type 4 TIC shapes. This study provides the rationale for future research to evaluate the utility of this approach in clinical practice.
18952896 A functional folate receptor is induced during macrophage activation and can be used to ta 2009 Jan 8 Previous work has demonstrated that a subset of macrophages expresses a folate receptor (FR) that can mediate internalization of folate-linked molecules, including imaging and therapeutic agents. To characterize this subset, macrophages were collected from peritoneal cavities of mice injected with saline, thioglycolate, zymosan, heat-killed or live bacteria, and cell-surface markers that coexpress with FR were identified. Virtually no F4/80(+) peritoneal macrophages from saline-injected mice expressed FR, whereas numerous macrophages from mice injected with each inflammatory stimulus expressed FR. Examination of cell differentiation antigens that are up-regulated in FR(+) macrophages revealed markers characteristic of an activated state (CD80, CD86, Ly-6C/G), whereas macrophages lacking these activation markers expressed few or no FR. FR(+) macrophages also produced tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species, and production of reactive oxygen species correlated linearly with expression of FR. Synovial macrophages collected from arthritic patients were found to bind and internalize folate-linked dyes. Moreover, a folate-linked radioimaging agent was shown to image inflamed joints of rheumatoid arthritic patients. These results suggest that FR constitutes a marker for macrophage activation and that FR(+) macrophages can be targeted with folate-linked drugs without promoting drug uptake by nonactivated macrophages. This trial was registered at www.clinicaltrials.gov as #NCT00588393.
19169963 Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammator 2009 Feb Novartis AG is developing canakinumab, an intravenously or subcutaneously infused, fully human mAb that neutralizes the bioactivity of human IL-1beta, which is involved in several inflammatory disorders. Canakinumab has promising clinical safety and pharmacokinetic properties, and demonstrated potential for the treatment of cryopyrin-associated periodic syndromes (CAPS) and possibly for other complex inflammatory diseases, such as rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis (SoJIA), COPD disease and ocular diseases. Currently in phase III clinical development, canakinumab was recently granted EU and US Orphan Drug status for SoJIA and CAPS. Early clinical trials have established the administration of canakinumab every 2 weeks to be safe and effective, offering a considerable advantage over the existing treatment with the human IL-1 receptor antagonist anakinra, which must be injected daily and which is often poorly tolerated by patients. The availability of more than one IL-1 targeting biological agent is undoubtedly advantageous, not only for patients and clinicians, but also for the elucidation of disease mechanisms.
19174034 [Abatacept in the treatment of active rheumatoid arthritis]. 2009 Jan 19 Abatacept (CTLA4Ig) is a human fusion protein which consists of a cytotoxic lymphocytic-associated type 4 antigen which is bound to the Fc part of the IgG1. Abatacept binds to CD80/CD86 on antigen-presenting cells thus blocking the co-stimulatory signal to the naïve T cells and interfering with a central inflammatory rheumatoid arthritis signal pathway.
20448290 Epitope spreading of the anti-citrullinated protein antibody response occurs before diseas 2010 Aug BACKGROUND: Anti-citrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA). OBJECTIVE: To investigate whether the recognition of citrullinated epitopes changes during disease onset or progression, by studying the fine specificity of ACPA in serum samples collected throughout the disease course, from before the onset of arthritis to longstanding RA. METHODS: Antibodies recognising five distinct citrullinated antigens were determined by enzyme-linked immunosorbent assay. Serum samples from 36 individuals who had donated blood before and after disease manifestation were used to investigate the development of citrullinated antigen recognition before disease onset. The association of ACPA reactivities with disease outcome was studied using sera from anti-cyclic citrullinated peptide-2 (CCP2)-positive patients with undifferentiated arthritis (UA) who did or did not progress to RA (UA-RA n=81, or UA-UA n=35). To investigate the ACPA recognition profile in patients with RA over a prolonged period of time, baseline serum samples from 68 patients were compared with samples obtained 7 years later. RESULTS: The number of recognised citrullinated peptides increased in the period preceding disease onset. At the time of disease manifestation, patients with UA who later developed RA recognised significantly more peptides than UA-UA patients. At later stages of the disease course, the ACPA fine specificity did not change. CONCLUSION: Epitope spreading with an increase in the recognition of citrullinated antigens occurs before the onset of RA. Immunological differences in ACPA fine specificity between UA-UA patients and UA-RA patients are present at baseline and are associated with the future disease course.
20405504 Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-al 2010 May Biologic therapy with tumor necrosis factor (TNF)-alpha antagonists for rheumatoid arthritis has been well established. We describe two patients with rheumatoid arthritis who developed chronic inflammatory demyelinating polyneuropathy (CIDP) during their course of therapy with TNF-alpha antagonists. A 45-year-old woman and a 49-year-old man, both with a history of rheumatoid arthritis, were treated with etanercept and infliximab, respectively. Clinical signs of peripheral neuropathy developed 2 weeks and 12 months after the initiation of TNF-alpha antagonists. Electrodiagnostic studies at variable points during the disease course showed signs of acquired demyelination consistent with CIDP. Cerebrospinal fluid examination showed albuminocytologic dissociation (total protein concentration 118 mg/dl and 152 mg/dl, respectively). Both patients failed to improve after discontinuation of the offending agent, and they responded poorly to corticosteroids. However, there was clinical and electrophysiologic recovery after initiation of intravenous immunoglobulin (IVIg) therapy. CIDP may occur early or late during the treatment course with TNF-alpha antagonists. IVIg may reverse and stabilize the inflammatory process.
20155319 The impact of ulcerative colitis on patients' lives compared to other chronic diseases: a 2010 Apr PURPOSE: This study was designed to identify the impact chronic ulcerative colitis (UC) has on the lives of patients compared to other chronic conditions. Overall, 451 patients with UC, 309 with rheumatoid arthritis, 305 with asthma, and 305 with migraine headaches were recruited in an Internet survey designed to assess a variety of disease-impact indices. RESULTS: Patients with UC reported a mean of eight (self-defined) flare-ups in the previous 12 months. Significantly more patients with UC (81%) believed that the quantity of flare-ups they experienced was 'normal', compared to patients with migraine headaches (64%) or asthma (75%). Patients with UC also reported significantly more worry about disease complications (84%), depression (62%), and embarrassment (70%) than patients with the other chronic conditions. CONCLUSIONS: Compared to patients with other chronic conditions, patients with UC perceive substantially more negative impact upon their lives, especially with regard to the psychological burden.
18684744 Dose-related patterns of glucocorticoid-induced side effects. 2009 Jul OBJECTIVE: To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. METHODS: Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5-7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. RESULTS: The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). CONCLUSION: The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit-risk ratio.
19995743 Role of interleukin 33 in human immunopathology. 2010 Jan Interleukin 33 (IL33) is a recently described member of the IL1 superfamily of cytokines. Originally defined on the basis of T-cell subset differentiation, IL33 is now recognised to mediate a wider role in regulating components of the innate immune response also, particularly via mast cell activation. In this paper the basic biology of IL33 is described together with that of its cognate receptor, ST2L, and the existing knowledge base for its potential role in mediating human pathology across a range of diseases is defined.
19894053 [Low-field magnetic resonance imaging for rheumatoid arthritis]. 2010 Feb Magnetic resonance imaging (MRI) as a cross-sectional imaging procedure allows a three-dimensional representation of musculature, ligaments, tendons, capsules, synovial membranes, bones and cartilage with high resolution quality. An activity assessment is further possible by application of a contrast medium (gadolinium-DTPA) to differentiate between active and chronic inflammatory processes. Evidence of a bone marrow edema detected by MRI in patients with rheumatoid arthritis (RA) can be interpreted as a prognostic and predictive factor for the development of bone erosions. On the basis of these advantages MRI is being employed more and more in the early diagnosis of inflammatory joint diseases. Semi-quantitative scores for analysis and grading of findings have already been developed and are in clinical use. Because MRI technical performances are invariably reproducible they can be practically retrieved in the course of examination which is particularly relevant in rheumatology. Therapy response or progression can thus be adequately displayed. Open, dedicated low-field MRI with a low signal strength of 0.2 Tesla (T) has been known since the 90s and now represents new MRI examination options in rheumatology. Smaller devices with lower acquisition and maintenance expenses as well as considerably more convenience due to the device itself result in a higher subjective acceptability by the patients as well as objectively more data records of low-field MRI scans of RA, which underline the significance of this new technical method. The German Society for Rheumatology (DGRh), represented by the Committee for "Diagnostic Imaging", meets this development with the release of recommendations and standards for the procedures of low-field MRI and their scoring and summarizes the most important technical data and information on clinical indications.
19211043 Predicting response to anti-TNF treatment in rheumatoid arthritis patients. 2009 Mar OBJECTIVE: To identify the clinical factors predicting failure or a good clinical response in the cohort of RA patients entered in the Lombardy Rheumatology Network (LORHEN) registry after 3 years of treatment with anti-TNF agents. METHODS: We studied the patients who had received anti-TNF agents and been followed up for a minimum of 6 months. Disease activity at baseline and after 6 months was assessed using the DAS28, and response was evaluated according to the EULAR improvement criteria. RESULTS: 1005 patients (55.72 years) were included in the analysis. at baseline the DAS-28 was 5.91+/-0.95 and a HAQ score was 1.46+/-0.61. At mean of 14.57 months, 29.9% of the patients achieved a DAS-28 of 3 DMARDs (AHR 0.077, 95% CI 0.58-1.03; p: 0.074), a high ESR (AHR 0.86, 95% CI 0.81-0.92; p: 0.000), Steinbrocker's functional class III/IV (AHR 0.66, 95% CI 0.48-0.90; p: 0.010), a high TJC (AHR 0.97, 95% CI 0.94-0.99; p: 0.011). A 12-month EULAR non-response was observed in 153/821 (18.6%) associated with a higher baseline HAQ score (AOR 1.51, 95% CI 1.03-2.20, p: 0.033), prior treatment with >3 DMARDs (AOR 1.76, 95% CI 1.09-2.85; p: 0.021) and corticosteroid >5 mg/day (AOR 2.05, 95% CI 1.06-3.97; p: 0.034). CONCLUSION: We found that only a minority of patients with long-standing RA treated with anti-TNF agents achieve a good clinical response or remission.
20740228 A fluopol-ABPP HTS assay to identify PAD inhibitors. 2010 Oct 14 Protein Arginine Deiminase (PAD) activity is dysregulated in numerous diseases, e.g., Rheumatoid Arthritis. Herein we describe the development of a fluorescence polarization-Activity Based Protein Profiling (fluopol-ABPP) based high throughput screening assay that can be used to identify PAD-selective inhibitors. Using this assay, streptonigrin was identified as a potent, selective, and irreversible PAD4 inactivator.
19015206 Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheum 2009 Jun BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Treatment with TNFalpha inhibitors reduces disease activity and improves outcomes for patients with RA. This study evaluated the efficacy and safety of certolizumab pegol 400 mg, a novel, poly-(ethylene glycol) (PEG)ylated, Fc-free TNFalpha inhibitor, as monotherapy in patients with active RA. METHODS: In this 24-week, multicentre, randomised, double-blind, placebo-controlled study, 220 patients previously failing > or =1 disease-modifying antirheumatic drug (DMARD) were randomised 1:1 to receive subcutaneous certolizumab pegol 400 mg (n = 111) or placebo (n = 109) every 4 weeks. The primary endpoint was 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 24. Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, health-related quality of life (HRQoL), pain and fatigue) and safety. RESULTS: At week 24, the ACR20 response rates were 45.5% for certolizumab pegol 400 mg every 4 weeks vs 9.3% for placebo (p<0.001). Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 (p<0.001). Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study. Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported. CONCLUSIONS: Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing > or =1 DMARD compared with placebo, and demonstrated an acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT00548834.
18762943 Adalimumab-induced noncaseating granuloma in the bone marrow of a patient being treated fo 2009 Feb Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration, primarily of the lungs and lymphatic system. While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed, the more widely used infliximab has demonstrated clear efficacy in this disease. The association between tumor necrosis factor (TNF)-inhibitors and noncaseating granulomas in the lung has been reported in literature. With the exception of one patient treated with adalimumab, who developed pulmonary granuloma, the remaining patients described in literature were treated with etanercept. The current case study is, to our knowledge, the first to describe adalimumab-induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although TNF-inhibitors are used in the treatment of granulomatous disorders, their use should be carefully monitored as, in rare cases, TNF-inhibitors may leave sufficient cytokine activation to support granuloma formation.
19437089 Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosi 2009 Sep Severe diarrhea improved dramatically with administration of the humanized anti-interleukin-6 receptor antibody tocilizumab (TCZ) in a patient with secondary reactive amyloidosis, which was associated with rheumatoid arthritis (RA). A 53-year-old woman with RA went into hypovolemic shock because of severe watery diarrhea associated with gastrointestinal amyloidosis. The high-dose prednisolone therapy and glucocorticoid pulse therapy did not improve her intractable diarrhea. After TCZ administration, the life-threatening diarrhea lessened in about 6 h, and her vital signs became stable the next day. Perforation of the small intestine, however, occurred 2 days after TCZ administration. Whether TCZ could have been involved in the perforation in such a short time is unknown. Surgery was successful, and the patient recovered. TCZ may work immediately in diarrhea associated with secondary amyloidosis.
19889051 Pseudolymphomatous reaction to varicella zoster virus vaccination: role of viral in situ h 2010 Oct Herpes zoster (shingles) is the result of a reactivation of the varicella zoster virus (VZV). Many adults obtain a VZV vaccine in order to prevent zoster. Non-specific injection site reactions and generalized herpes eruptions have been reported to occur, especially in immunocompromised patients. However, these are most often anatomically generalized reactions and histopathologically resemble typical herpes infections. We report a 61-year-old female on immunosuppressant medications for rheumatoid arthritis who presented with a subcutaneous nodule at the site of a recent herpes zoster vaccination. Histopathological examination revealed a dense nodular and interstitial mononuclear infiltrate throughout the mid and deep dermis with extension into the superficial subcutaneous fat. Immunohistochemical staining revealed an admixture of T-cells and B-cells, with a predominance of T-cells. These findings are consistent with a pseudolymphoma (PL), a reactive inflammatory disorder that can resemble cutaneous lymphoma and has rarely been described in herpes infections and post-herpetic scars. In situ hybridization studies for VZV were performed and highlighted occasional deep fibroblasts with nuclear positivity for VZV DNA. A review of post-vaccination reactions and herpes-related PL is discussed with emphasis on using in situ hybridization in establishing the diagnosis.
20514908 Pregnancy course and neonatal outcome after exposure to leflunomide--2 cases report and re 2009 Leflunomide (LMF) is an immunemodulatory drug used in the therapy of Rheumatoid Arthritis (RA). After oral administration in the mucosa of digestive tract LMF is quickly converted to an active metabolite A77126 which is a competitive inhibitor of dihydroorotate dehydrogenase--enzyme required in pirymidyne synthesis resulting in decreased proliferation of T and B lymphocytes. As animal studies showed A77126 embryo- and fetotoxity and no relevant epidemiological research in humans were available, LMF received category X pregnancy destination. This is a detailed presentation of two pregnancy cases during LMF therapy in Poland. The first patient was a multiparous woman suffering from RA for 17 years and treated with LM during the last 16 months. The second woman was a primigravida with RA diagnosed 4 years ago and treated with LMF for the last 20 months. LMF wash-out procedures were started immediately as the patients referred with diagnosed early pregnancies with oral administration of 8g of cholestyramine tid for 11 days. After completing the procedure the patients were referred to the Gynecology and Obstetrics Department. The first pregnancy successfully finished with a vaginal delivery of a completely healthy, female newborn of 2540g at the 41st gestational week and the second patient also delivered vaginally a healthy female newborn of 3200g at 39th week of pregnancy.
20544244 When should we use parenteral methotrexate? 2010 Oct Oral methotrexate is the benchmark against which other disease-modifying anti rheumatic drugs are measured. The use of parenteral methotrexate for those failing to tolerate or respond to oral therapy is accepted, but indications for its use and its place in the therapeutic ladder have not been fully investigated. We assessed the use of parenteral methotrexate (MTX) in our rheumatoid arthritis (RA) population and compared the characteristics of these patients to a matched group of those on oral therapy. We compared response rates to each approach using DAS 28 scores, ESR and visual analogue scales. Inferences on costs of parenteral therapy were made and predictors of response defined. We found that 10% of our total RA patient population were on parenteral methotrexate, having failed to tolerate or respond to oral therapy. Seventy-five percent of these met the criteria for the use of anti-tumour necrosis factor (TNF) agents. Overall response rates were equivalent to those obtained by responders to oral MTX. Patients on parenteral therapy were younger and were more likely to have extreme values of body mass index (BMI) than those on oral therapy. The approach was economically viable, although many patients unnecessarily attended hospital to receive their injections. We advocate consideration of parenteral MTX in all RA patients unresponsive to oral therapy prior to treatment with anti-TNF therapy. Response to parenteral therapy can be predicted by low BMI (below 22 kg/m(2)), possibly as a result of malabsorption, or by high BMI (over 30) as a result of gastrointestinal intolerance. A mechanism to deliver this option through self-administration in the community should be encouraged.
20346243 Three-dimensional volumetric ultrasonography. Does it improve reliabililty of musculoskele 2010 Jan OBJECTIVE: To compare the interobserver reliability of three-dimensional (3D) volumetric ultrasonography (US) and 2D real-time US in detecting inflammatory and destructive changes in rheumatoid arthritis (RA) wrist and hand. METHODS: Two RA patients were selected by a rheumatologist who performed independently a grey-scale and power Doppler (PD) volumetric acquisition at three anatomic sites in their more symptomatic wrist/hand using two identical scanners equipped with 3D volumetric probe. Twelve rheumatologists expert in MSUS were randomly assigned to a US scanner and a patient. In the first part of the study, each group of experts blindly, independently, and consecutively performed a 2D real-time grey-scale and PD US investigation of inflammatory changes and/or bone erosions at the three anatomic sites. In the second part of the study, each group of investigators blindly evaluated the same pathologic changes in the 6 volumes from the patient not scanned by them. RESULTS: The kappa values were higher for 3D volumetric US than for 2D US in the detection of synovitis/tenosyno-vitis (0.41 vs. 0.37) and PD signal (0.82 vs 0.45) and in the PD signal grading (0.81 vs. 0.55). CONCLUSION: 3D volumetric US may improve the interobserver reliability in RA multicentre studies.
20555144 GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis i 2010 Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer's disease (AD). While it has been commonly assumed that RA patients' usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. To determine whether intrinsic factors within RA pathogenesis itself may underlie RA's protective effect, we investigated the activity of colony-stimulating factors, upregulated in RA, on the pathology and behavior of transgenic AD mice. 5 microg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factors (M-CSF, G-CSF, or GM-CSF) were administered unilaterally into the hippocampus of aged cognitively-impaired AD mice and the resulting amyloid load reductions determined one week later, using the artificial cerebrospinal fluid-injected contralateral sides as controls. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. 20 daily subcutaneous injections of 5 microg of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) were administered to balanced cohorts of AD mice after assessment in a battery of cognitive tests. Reductions in amyloid load and improvements in cognitive function were assessed. Subcutaneous GM-CSF administration significantly reduced brain amyloidosis and completely reversed the cognitive impairment, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, recombinant human GMCSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.