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ID PMID Title PublicationDate abstract
17988587 [Changes of serum BAFF and IL-21 levels in patients with systemic lupus erythematosus and 2007 Nov AIM: To investigate the changes of serum BAFF and IL-21 levels in the patients with systemic lupus erythematosus (SLE) and explore their clinical significance. METHODS: The serum levels of BAFF and IL-21 were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The levels of serum BAFF and IL-21 in the patients with SLE were obviously higher than those in healthy control group. The BAFF level in the group of lupus nephritis (LN) with renal biopsy increased with pathologic aggravation and the IL-21 level in II, III, IV LN also increased, with the most obviously change in the type IV. The levels of BAFF and IL-21 obviously increased in SLE patients with Sjogren's syndrome (SS), but the levels of BAFF and IL-21 obviously tended to decrease in the patients after glucocorticosteroid treatment for a week, with the most significant decrease in BAFF. The changes of BAFF and IL-21 were related to major immune indexes in the patients with SLE. There was positive correlation between BAFF and IL-21 in IV LN. CONCLUSION: The levels of serum BAFF and IL-21 level are increased in the patients with SLE. The dysfunction and synergistic effect of T and B lymphocytes play different roles in the patients with different organ damage and pathoprocess respectively.
16344495 Immunological consequences of thalidomide treatment in Sjögren's syndrome. 2006 Jan OBJECTIVE: To study the immunological consequences of systemic thalidomide treatment in patients with Sjögren's syndrome. METHODS: Cytokine (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 6) and soluble receptor (sIL2R) levels were measured in patient and control plasma (n = 7), before and after thalidomide treatment. Peripheral blood mononuclear cells were examined by FACS analysis for potential changes in specific cell populations (T cells, B cells, monocytes), and for the expression of activation markers (CD25, HLA-DR), costimulatory molecules (CD40, CD40L), TNF receptors, chemokine receptors, and adhesion molecules (L-selectin (L-sel)). RESULTS: Owing to adverse effects of thalidomide, the treatment interval was limited. None the less, statistically significant changes in markers of cell activation were recorded in the four treated patients. Before treatment, HLA-DR, TNFRI, CXCRI, and CXCRII were raised in the patients compared with healthy controls (p<0.05) and their expression was down regulated after treatment. B cell numbers and expression of the adhesion molecule L-sel also declined with thalidomide. CONCLUSION: Significant changes in measures of cell activation were detected during thalidomide treatment within this limited study, which upon further investigation may offer insight into the underlying immunoregulatory pathways of thalidomide.
17289835 (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrol 2007 May (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of interleukin (IL)-1beta and IL-18, but it had little effect on the release of several other cytokines, including IL-1alpha, tumor necrosis factor-alpha, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis, and it did not affect the proliferation of activated primary T cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice, and it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.
18292102 Can clinical factors at presentation be used to predict outcome of treatment with methotre 2009 Jan PURPOSE: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. METHODS: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. RESULTS: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). CONCLUSIONS: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.
19004030 MAGE-B2 autoantibody: a new biomarker for pediatric systemic lupus erythematosus. 2008 Dec OBJECTIVE: Melanoma-associated antigen gene B2 (MAGE-B2) encodes an embryonic antigen normally silenced after birth except in testis and placenta. We identified the MAGE-B2 gene and autoantibodies in pediatric patients with systemic lupus erythematosus (SLE) glomerulonephritis. We investigated the prevalence of MAGE-B2 autoantibodies in association with active SLE, to determine a pathogenetic role of MAGE-B2 protein through its distribution in cells and tissues. METHODS: A cross-sectional study analyzed the frequency of MAGE-B2 autoantibodies in 40 patients with pediatric SLE, 23 adult controls, and 16 patients with pediatric juvenile rheumatoid arthritis (JRA) using Western blots containing recombinant MAGE-B2. SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG) index measured SLE disease activity. Tissue distribution of MAGE-B2 protein was assessed by immunohistochemistry, immunofluorescence, and Western blots. RESULTS: Seventeen (43%) of 40 pediatric SLE patients had MAGE-B2 autoantibodies as compared to 0 of 16 JRA patients and 2 of 23 adult controls. SLE disease activity was significantly higher in MAGE-B2 autoantibody-positive versus autoantibody-negative patients (SLEDAI-2K, mean 10.9 vs 5.2, p = 0.013; BILAG, mean 15.3 vs 6.3, p = 0.023). Active nephritis was more prevalent (60% vs 24%) in MAGE-B2 autoantibody-positive than autoantibody-negative SLE patients. MAGE-B2 protein was visualized in SLE kidney proximal convoluted tubules and in tumor epithelial cells, but not in lymphoblastoid cells. CONCLUSION: MAGE-B2 autoantibody appears to be a clinically relevant biomarker for pediatric SLE disease activity and nephritis.
17888166 Erosive arthropathy in systemic sclerosis. 2007 Sep 22 BACKGROUND: To determine radiological features of arthropathy in systemic sclerosis patients with polyarthritis. RESULTS: Forty one women and 5 men were included in this study. The mean age was 41 + 14,2 years, the mean duration of disease was 10,5+ 6,5 years. Thirty seven patients (80%) had radiological abnormalities including joint space narrowing (37%) and erosions (43%). At presentation, the prevalence of radiological foot abnormalities was lower than that of hands (26% vs 79%, p < 0,001). There was no significant difference between patients with (n = 24) and without erosive arthropathy (Joint space narrowing and/or erosion) (n = 22) in terms of cutaneous subtype, organ involvement, calcinosis presence of rheumatoid factor, ANA, Anti-topoisomerase antibodies. CONCLUSION: This study showed an high frequency of erosive arthropathy in our Morroccan SSc patients with clinical synovitis.
17853950 Retrospective review of pediatric and adult autoimmune hepatitis in two quaternary care ce 2007 Sep BACKGROUND: It has been previously reported that British Columbia's (BC's) First Nations (Aboriginal) community has an increased risk of autoimmune diseases, including rheumatological conditions (rheumatoid arthritis, systemic lupus) and primary biliary cirrhosis. The researchers hypothesized that this community may also be at increased risk for autoimmune hepatitis (AIH). METHODS: Independent, retrospective reviews of the databases of two separate tertiary/quaternary British Columbia university-affiliated health care institutions, the Adult Liver Transplant Program of the BC Transplant Society and the Division of Pediatric Gastroenterology, BC Children's Hospital (Vancouver, BC), were performed. All patients referred with a diagnosis of probable or definite AIH who identified themselves as being of First Nations descent from 1988 to 2004 were reviewed. The liver transplant database records all adult patients in the province referred for transplant assessment. The pediatric database records all children referred to the BC Children's Hospital. RESULTS: A total of 68 adult patients with a definite or probable diagnosis of AIH were referred to the liver transplant program. Twelve patients (17.6%) were Aboriginal, 11 of which were female. Similarly, a total of 30 children with probable or definite AIH were identified from the pediatric database. Six of these cases (20%) were identified in Aboriginal children. CONCLUSIONS: The findings suggest an increased prevalence of AIH among BC's First Nations community. A disproportionate First Nations representation was found on independent review of two databases. Future studies are needed to determine the true prevalence of AIH in this community, and to uncover the genetic predisposition and the environmental triggers explaining this phenomenon.
16368978 Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pyl 2006 Jan Besides various gastroduodenal diseases, Helicobacter pylori infection may be involved in autoimmune disorders like rheumatoid arthritis (RA) or idiopathic thrombocytopenic purpura. Such autoimmune disorders are often associated with autoreactive antibodies produced by B-1 cells, a subpopulation of B lymphocytes. These B-1 cells are mainly located in the pleural cavity or mucosal compartment. The existence of H. pylori urease-specific immunoglobulin A (IgA)-producing B cells in the mucosal compartment and of their specific IgM in the sera of acutely infected volunteers suggests the possibility that urease stimulates mucosal innate immune responses. Here, we show for the first time that purified H. pylori urease predominantly stimulates the B-1-cell population rather than B-2 cells, which produce antigen-specific conventional antibodies among splenic B220(+) B cells. The fact that such stimulation of B-1 cells was not affected by the addition of polymyxin B indicates that the effect of purified H. pylori urease was not due to the contamination with bacterial lipopolysaccharide. Furthermore, the production of various B-1-cell-related autoreactive antibodies such as IgM-type rheumatoid factor, anti-single-stranded DNA antibody, and anti-phosphatidyl choline antibody was observed when the splenic B cells were stimulated with purified H. pylori urease in vitro. These findings suggest that H. pylori components, urease in particular, may be among the environmental triggers that initiate various autoimmune diseases via producing autoreactive antibodies through the activation of B-1 cells. The findings shown here offer important new insights into the pathogenesis of autoimmune disorders related to H. pylori infection.
19107015 [Tuberculosis, anti-TNF agents and other immunosuppressants: evolution of preventitive str 2008 Dec The occurrence of tuberculosis (TB) in patients treated with immunosuppressive drugs (ISD) is an old problem that has been highlighted by cases occurring in patients using anti-TNFalpha drugs. After a brief review of anti-tuberculosis immunity to highlight the immunosuppressant targets, we show how an epidemiological approach allows the control of risk in patients with drug-induced immunosuppression. The assessment and the control of this risk are usually complicated by underlying immunosuppressant disease, co-morbidities, associated drugs and local disease prevalence. Steroid therapy in systemic diseases and ISD protocols in graft rejection prevention illustrate this problem particularly well. The management strategy adopted to combat anti-TNF related tuberculosis in rheumatoid arthritis (RA) has allowed these biases to be avoided. The incidence of TB in RA has been recorded in some national databases (USA, Spain). A four fold increase was registered after the introduction of anti-TNF agents in 2001 which could be considered as the true risk of the drug. Several national health agencies proposed guidelines to screen and prevent TB risk in these patients. Their effectiveness was confirmed by the incidence of TB returning the level prior to the introduction of these agents. Recommendations could be improved by using interferon-gamma screening tests and a better benefit/risk prophylaxis. They should be observed and if possible extended to new and other ISD.
17604367 Exacerbation of ulcerative colitis after rituximab salvage therapy. 2007 Nov BACKGROUND: B-cells are considered to play a pathogenic role in human ulcerative colitis (UC) by producing autoantibodies that cause epithelial cell damage. Here we report on a patient with intractable UC who suffered from a severe exacerbation of UC after salvage therapy with rituximab, a B-cell-depleting anti-CD20-antibody. METHODS: A 58-year-old patient with active long-standing UC and unresponsiveness or adverse events to mesalamine, corticosteroids, azathioprine, methotrexate, infliximab, leukapheresis, mycophenolate mofetil, and adalimumab received 375 mg/m(2) rituximab. RESULTS: A severe exacerbation of UC activity was noted upon therapy that required hospitalization. Subsequent studies showed a complete depletion of CD20-positive mucosal B-cells associated with a suppression of local IL-10 production. CONCLUSIONS: In contrast to rheumatoid arthritis patients, rituximab had deleterious effects in our UC patient by blocking IL-10 producing B-cells. Our data suggest an important anti- rather than proinflammatory role of B-cells in UC.
18500464 Systemic reduction of soluble complement receptor II/CD21 during pregnancy to levels remin 2008 Sep Complement receptor type II/CD21 is the functional receptor for complement fragments such as C3d, iC3b and the Epstein Barr Virus. A soluble form of CD21 (sCD21) is shed from lymphocytes surface and is able to bind to its ligands found in the plasma. The amount of sCD21 in serum may modulate immunity as the plasma levels are correlated with autoimmune conditions, such as Systemic Lupus Erythematosus, Rheumatoid Arthritis and Sjoegren's Syndrome. Because of the fact that pregnancy may lead to remission of autoimmune diseases we determined the serum levels of sCD21 during pregnancy and postpartum. The serum sCD21 levels during pregnancy are significantly lower as compared to that of the healthy controls. There were no significant differences in sCD21 levels between the mother and the cord blood also immediately after parturition. Restoration of sCD21 levels to normal values takes between 6 weeks and 1 year after childbirth. Our study indicates that CD21-shedding is affected during pregnancy comparable to that of autoimmunity.
18433944 [Diagnosis of early spondyloarthritis]. 2008 Jul PURPOSE: Spondyloarthritis (SpA) encompass different diseases with common characteristics, ankylosing spondylitis (AS) being the most typical. Undifferentiated SpA may evolve into AS. In France, SpA and rheumatoid arthritis could have the same prevalence. AS has a profound impact on the quality of live and function of patients as well as social and economic consequences for the society. KEY POINTS: There is a mean delay of five to eight years between onset of symptoms and diagnosis of AS. This is due to the fact that radiographic sacroiliitis is delayed. The purpose of an earlier diagnosis is emphasized by the need for a better management, the new diagnostic method including magnetic resonance imaging and ultrasonography, and by the efficacy of anti-TNF therapy. The current criteria (New-York, Amor, ESSG) are classification but not diagnostic criteria. Their sensitivity is insufficient for an early diagnosis of SpA. Several groups are studying methods to ensure an early diagnosis. The group of Berlin has proposed, for patients suffering inflammatory chronic back pain, an algorithm using clinical, radiological and biological signs with, if necessary, search of HLA-B27 and MRI of sacroiliac joints. But this system is theoretical and the group of Maastricht found it of little effectiveness. Furthermore, it does not take account patients with symptoms beginning out of the spine. CONCLUSION: We believe that only the follow-up of cohorts constituted of patients with early SpA will enable us to improve our knowledge regarding diagnostic criteria and new tools for early diagnosis, as well as outcome, prognosis and early management of SpA and AS.
18393777 Recent clinical trials of cladribine in hematological malignancies and autoimmune disorder 2006 Jan The purine nucleoside analog - cladribine (2-chlorodeoxyadenosine, 2-CdA) is a cytotoxic agent with high activity in lymphoid and myeloid malignancies. It is also an effective drug in some autoimmune disorders. 2-CdA is usually administered intravenously in continuous or 2-hour infusion. Recently however, new formulation of this agent has been developed for subcutaneous and oral administration. 2-CdA is widely established as first line standard treatment for hairy cell leukemia. Moreover several clinical trials have demonstrated that this agent, used alone or in combination with other cytotoxic drugs, showed good efficacy and acceptable toxicity profile in the treatment of chronic lymphocytic leukemia, Waldenström macroglobulinemia, low-grade non-Hodgkin's lymphoma and acute myeloid leukemia. Moreover, some studies indicate that 2-CdA has some activity in progressive multiple sclerosis and other autoimmune disorders including autoimmune hemolytic anemia, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and in patients with refractory factor VIII inhibitors. This review article will summarize the results of recent clinical trials with 2-CdA in hematological malignancies, multiple sclerosis and other autoimmune diseases.
18336732 Periodate oxidized ATP (oATP) reduces hyperalgesia in mice: involvement of P2X7 receptors 2008 Jan Some inflammatory mediators play an important role not only in the pathogenesis of the inflammatory pain, but also in that of neuropathic and visceral pain. We previously showed the antihyperalgesic effect of oATP, the inhibitor of the P2X7 receptors for the pro-nociceptive ATP, in experimental inflammation. Here we show the antihyperalgesic effect of oATP in mouse models of neuropathic and visceral pain, other than in a model of arthritic pain mimicking rheumatoid arthritis in humans. We also show that mice lacking P2X7 receptors (KO) are resistant to hyperalgesic thermal stimuli following the induction of arthritic, neuropathic and visceral pain. Local (injection into the right hind paw) pre-treatment with oATP is able to prevent the successive induction of ATP-dependent hyperalgesia in wild type mice. In addition, KO mice are not insensitive to intraplantar treatment with ATP. Our data suggest that, even if oATP is able to inhibit purinoceptors different from P2X7, the latter are the more important involved in pain transmission.
18257403 [Transcription factor KLF2 (Krüppel-like factor 2) and natural defence of vascular endoth 2007 Vascular endothelium, monocytes and T-lymphocytes belong to the key cellular populations, which take an active part in the host's defence reactions. A successful course of these reactions is determined by a meticulous control of all phases since the very first steps until final healing of all incurred wounds. Any failure of the control mechanisms may lead to the development of chronic inflammatory diseases with an autoimmune component, such as the rheumatoid arthritis or atherosclerosis. An inflammatory reaction which is already under way is regulated by anti-inflammatory cytokines. However, of equal importance is the maintenance of cellular participants of inflammatory reactions in a quiescent state while no pro-inflammatory stimuli are present. One of the most important endogenous mediators, which prevent a self-initiated activation of endothelial cells, monocytes and T-lymphocytes, is represented by the transcription factor Krüppel-like factor 2. Its impact on the mentioned cells is almost identical with the so-called pleiotropic effects of inhibitors of the enzyme HMG CoA reductase or statins. This review article offers an insight into basic preventive mechanisms exerted by KLF2, notably those related to atherosclerosis.
18045138 Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lesso 2007 The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.
17714525 Oral infections and systemic disease--an emerging problem in medicine. 2007 Nov The relationship between oral and general health has been increasingly recognised during the past two decades. Several epidemiological studies have linked poor oral health with cardiovascular disease, poor glycaemic control in diabetics, low birth-weight pre-term babies, and a number of other conditions, including rheumatoid arthritis and osteoporosis. Oral infections are also recognised as a problem for individuals suffering from a range of chronic conditions, including cancer and infection with human immunodeficiency virus, as well as patients with ventilator-associated pneumonia. This review considers the systemic consequences of odontogenic infections and the possible mechanisms by which oral infection and inflammation can contribute to cardiovascular disease, as well as the oral conditions associated with medically compromised patients. A large number of clinical studies have established the clinical efficacy of topical antimicrobial agents, e.g., chlorhexidine and triclosan, in the prevention and control of oral disease, especially gingivitis and dental plaque. The possible risks of antimicrobial resistance are a concern, and the benefits of long-term use of triclosan require further evaluation. Oral infections have become an increasingly common risk-factor for systemic disease, which clinicians should take into account. Clinicians should increase their knowledge of oral diseases, and dentists must strengthen their understanding of general medicine, in order to avoid unnecessary risks for infection that originate in the mouth.
17680518 Ultrasound in finger joints: findings in normal subjects and pitfalls in the diagnosis of 2007 Aug PURPOSE: Grey-scale ultrasound may be used to visualise the amount of synovial tissue in patients with rheumatoid arthritis (RA). Different scoring systems have been developed. None of the scoring systems have been tested on a larger group of healthy joints, and it is therefore unknown to what extent synovial tissue is seen on grey-scale ultrasound in healthy joints. The objective of this study was to test two scoring systems on healthy volunteers. MATERIALS AND METHODS: 24 healthy men and women between 30 and 54 years underwent scanning of the MCP, PIP and DIP joints of their dominant hand. Each person was scanned in 69 positions. The images were graded on a scale from 0 to 4 with two scoring systems (I and II). Scores 0 - 1 were defined as normal and 2 - 4 as pathological. With scoring system I, only markedly hypoechoic synovium was graded. With scoring system II, marked hypoechogenicity was not a criterion. RESULTS: With system I, 89 % of the joints obtained at least one pathological score. With system II, 95 % of the joints obtained at least one pathological score. With both systems, women obtained higher scores than men, and the number of high scores increased with increasing age. CONCLUSION: An unacceptably high number of joints obtained pathological scores with both scoring systems in healthy volunteers. This indicates that many of the scores interpreted as pathological in patients with RA may just be normal findings, with increasing numbers in older patients.
17355199 Chemical genetic transcriptional fingerprinting for selectivity profiling of kinase inhibi 2007 Feb The importance of protein kinases as a major class of drug targets across multiple diseases has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors. Bruton's tyrosine kinase (Btk) is a compelling drug target in multiple therapeutic areas, including systemic lupus erythematosus, asthma, rheumatoid arthritis, and B cell malignancies. We have combined potent, selective kinase inhibition through chemical genetics with gene expression profiling to identify a "fingerprint" of transcriptional changes associated with selective Btk kinase inhibition. The Btk transcriptional fingerprint shows remarkable relevance for Btk's biological roles and was used for functional selectivity profiling of two kinase inhibitor compounds. The fingerprint was able to rank the compounds by relative selectivity for Btk, and revealed broader off-target effects than observed in a broad panel of biochemical kinase cross screens. In addition to being useful for functional selectivity profiling, the fingerprint genes are themselves potential preclinical and clinical biomarkers for developing Btk-directed therapies.
17042026 Personal impact of disability in osteoarthritis: patient, professional and public values. 2006 Sep BACKGROUND: Osteoarthritis (OA) is a leading cause of disability. Numerous tools are available to assess this, but they fail to place a patient value upon disability. In rheumatoid arthritis, research has shown patients have different importance values for similar disabilities, and these individual values can be used to weight disability levels, creating a measure of personal impact. OBJECTIVES: Firstly, to determine if the Health Assessment Questionnaire (HAQ) can be used as the basis for an importance value scale by assessing if it includes activities considered important by OA patients. Secondly, to determine if the weights used for the value scale should be based on population, healthcare professional or patient values. METHOD: Twenty-five OA patients, 25 healthy controls and 25 healthcare professionals rated the importance of the items on the HAQ and shortened Modified HAQ (MHAQ). Prior to completing the HAQ, patients generated a list of activities that were important to them. RESULT: The HAQ contained 69% of items that patients considered important. No items were consistently deemed unimportant by patients. There was low agreement within and between groups about the importance of the items on the HAQ and MHAQ. CONCLUSION: The HAQ is a suitable basis for a value scale for an OA disability impact score. Importance values for function differed for patients, healthcare professionals and the general population; therefore individual patient weightings need to be used. Further work is under way to validate a measure of the personal impact of disability in patients with lower limb OA.