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ID PMID Title PublicationDate abstract
16624928 Is there a role for TNF-alpha in anti-neutrophil cytoplasmic antibody-associated vasculiti 2006 May Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is the most common cause of rapidly progressive glomerulonephritis and immune-mediated pulmonary renal syndrome. Now that the acute manifestations of the disease generally can be controlled with immunosuppressive drugs, ANCA-associated vasculitis has become a chronic and relapsing inflammatory disorder. The need to develop safer and more effective treatment has led to great interest in the mediators of chronic inflammation. There are many lessons to be learned from studies of other chronic inflammatory diseases, particularly rheumatoid arthritis (RA). The identification of a TNF-alpha-dependent cytokine cascade in the in vitro cultures of synovium in joints of patients with RA led to studies of TNF blockade in experimental models of arthritis and subsequently to clinical trials. These have culminated in the widespread introduction of anti-TNF therapy not only in RA but also in Crohn disease, ankylosing spondylitis, and several other chronic inflammatory disorders. Following a similar investigative pathway, studies that show the importance of TNF production by leukocytes and intrinsic renal cells in glomerulonephritis have been followed by the demonstration of the effectiveness of TNF blockade in several experimental models of glomerulonephritis and vasculitis. In experimental autoimmune vasculitis, improvement in disease was paralleled by a reduction in leukocyte transmigration, as demonstrated by intravital microscopy. The benefit of infliximab (a mAb to TNF) in ANCA-associated vasculitis was recently reported in a prospective open-label study. However, the use of etanercept (a soluble TNF receptor fusion protein) was not found to be of significant benefit in a randomized, controlled trial in patients with Wegener granulomatosis. Therefore, there is a need for further evaluation of the use of anti-TNF antibodies in patients with ANCA-associated glomerulonephritis.
18625446 Autoimmunity and oxidatively modified autoantigens. 2008 Jul Oxidative damage mediated by reactive oxygen species results in the generation of deleterious by-products. The oxidation process itself and the proteins modified by these molecules are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Proteins modified in this manner have been shown to induce pathogenic antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM) and rheumatoid arthritis (RA). 8-oxodeoxyguanine (oxidatively modified DNA) and oxidized low-density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE) modified 60 kD Ro autoantigen induces an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. The administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, particularly on account of the overwhelming evidence for the involvement of oxidative damage in autoimmunity. However, this should be viewed in the light of disappointing results obtained with the use of antioxidants in cardiovascular disease.
18609734 No improvement in survival of patients with amyloidosis associated with inflammatory rheum 2008 Jul OBJECTIVE: To assess the incidence and outcome of renal replacement therapy (RRT) among patients with amyloidosis associated with inflammatory rheumatic diseases. METHODS: Patients with amyloidosis entering RRT from 1987 to 2002 were identified from the Finnish Registry for Kidney Diseases. Five hundred two patients were identified, 80% of whom had amyloidosis associated with an underlying rheumatic disease. They were followed from the time of entering RRT until death or until the end of 2003 using the Finnish national mortality files. RESULTS: During the study period, there was no decline in the number of patients with amyloidosis entering RRT. Mean age of patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) increased significantly from 1987 to 2002 (p < 0.001). Male sex and a diagnosis of JIA indicated an increased risk of mortality. The median survival time after entering RRT was 2.11 years for RA (95% CI 1.93 to 2.69), 2.37 years for ankylosing spondylitis (95% CI 1.11 to 4.31), and 3.05 years for JIA (95% CI 2.19 to 4.23). The 5-year survival rates among patients with the corresponding diagnoses were 18% (95% CI 14% to 23%), 30% (95% CI 14% to 48%), and 27% (95% CI 14% to 41%), respectively. CONCLUSION: No decline was seen in the number of patients with amyloidosis associated with inflammatory rheumatic diseases accepted for RRT, but over the years, the age of patients with RA or JIA entering RRT was seen to increase. The outcome of patients with amyloidosis and endstage renal disease associated with rheumatic diseases remains poor.
17934097 alpha-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs. 2007 Nov alpha-Melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide derived from the proopiomelanocortin by post-translational processing. In addition to its effects on melanocytes, alpha-MSH has potent anti-inflammatory effects when administered systemically or locally. The anti-inflammatory effects of alpha-MSH are mediated by direct effects on cells of the immune system as well as indirectly by affecting the function of resident non-immune cells. alpha-MSH affects several pathways implicated in regulation of inflammatory responses such as NF-kappaB activation, expression of adhesion molecules and chemokine receptors, production of pro-inflammatory cytokines and other mediators. Thus alpha-MSH may modulate inflammatory cell proliferation, activity and migration. The anti-inflammatory effects of alpha-MSH have been confirmed by means of animal models of inflammation such as irritant and allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, ocular and brain inflammation. Most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tripeptide KPV. K(D)PT, a derivative of KPV corresponding to the amino acid 193-195 of IL-1beta, is currently emerging as another tripeptide with potent anti-inflammatory effects. The anti-inflammatory potential together with the favourable physiochemical properties most likely will allow these agents to be developed for the treatment of inflammatory skin, eye and bowel diseases, allergic asthma and arthritis.
17611984 Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from 2007 Aug OBJECTIVE: To investigate whether 14-3-3 proteins were detectable in synovial fluid (SF) of patients with inflamed joints, and if so, what isoform(s); and to examine whether there was a correlation between the levels of these proteins and those of MMP-1 and MMP-3 in the same samples. METHODS: In general, 2 sets of synovial and serum samples were analyzed. The first set of 17 SF -samples from patients with inflamed joints were analyzed for 14-3-3 eta isoform by Western blot. The second set of 12 matching serum and SF samples were analyzed for 14-3-3 eta, gamma, MMP-1, and MMP-3 by the same procedure. The MMP-1 stimulatory effect of various concentrations of 14-3-3 eta in cultured fibroblasts was then evaluated. RESULTS: We found that of the seven 14-3-3 isoforms tested (beta, gamma, epsilon, eta, sigma, Theta, and zeta), the levels of only 2 isoforms, eta and gamma, were easily detectable in SF samples from patients with inflammatory joint diseases. The levels of these proteins were significantly higher in inflammatory SF and serum samples relative to controls. The values of these proteins correlated strongly with the levels of MMP-1 and MMP-3, 2 biomarkers for rheumatoid arthritis, detected in sera. Further, the level of 14-3-3 eta was significantly higher in a pool of 12 serum samples from patients with inflammatory joint disease than those from healthy individuals. CONCLUSION: Detection of only 2 (14-3-3 eta and gamma) out of 7 different isoforms in SF suggests they are specific to the site of inflammation, and that distinguishes them from barely detectable levels of these isoforms found in normal serum. The MMP-1 stimulatory effect of the eta isoform explains its correlation with MMP-1 levels seen in these samples.
17571910 New dosage formulations for targeted delivery of cyclo-oxygenase-2 inhibitors: focus on us 2007 NSAIDs are a widely used class of analgesic and anti-inflammatory drugs that act by inhibiting the cyclo-oxygenase (COX) enzyme. However, because of their nonspecificity of action, use of these agents as long-term therapy for chronic pain in diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA) is often discouraged. Among NSAIDs, COX-2 inhibitors are promising candidates for long-term therapy of chronic diseases, particularly in the elderly, because of their reduced incidence of gastrointestinal adverse effects. However, in recent times these agents have also been shown to cause adverse effects such as cardiovascular effects (myocardial infarction, stroke and hypertension) and renal effects (decreased renal blood flow/glomerular filtration rate), which in 2004 led to the withdrawal of rofecoxib and in 2005 the withdrawal of valdecoxib from the US market. Importantly, these adverse effects can be effectively reduced by achieving site specific/targeted delivery through new formulation approaches. These formulations not only restrict the drug supply to specific organs but also reduce the dose required. As a result, use of new delivery systems such as nanoparticles, microparticles, microemulsions and nanogels has gained widespread applicability in the management of chronic disease, especially in the elderly, and particularly when there is a need to decrease dose-dependent adverse effects (as is the case with COX-2 inhibitors). This article reviews various new approaches to the delivery of COX-2 inhibitors and highlights issues related to the development of delivery systems for these agents for RA, OA, cancer (familial adenomatous polyposis, prostate, breast and non-small cell lung cancer), ocular diseases (such as diabetic retinopathy) and inflammatory diseases of the skin, with emphasis on their potential for use in the elderly. Emphasis is also placed on the preparation of these particulate systems, their release profile and behaviour in biological systems.
17420690 Tumor necrosis factor antagonists: preliminary evidence for an emerging approach in the tr 2007 Apr The anti-tumor necrosis factor (TNF) monoclonal antibody infliximab and the soluble TNF receptor etanercept inhibit the pleiotropic actions of TNF and are widely used for the treatment of rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), spondyloarthropathies (SpA), Crohn's disease, and psoriasis with an acceptable safety profile. A pathogenetic role of TNF in ocular inflammatory conditions has recently emerged from small trials reporting preliminary results on the efficacy of these agents in patients with noninfectious uveitis, regardless of the origin of the disease. The authors review the published experience, derived mostly from investigator-sponsored trials and uncontrolled case series, on the use of TNF antagonists in approximately 280 patients with various ocular conditions who were inadequately controlled on currently available therapy. These reports suggest that TNF antagonists, mainly infliximab, which may have better efficacy than etanercept, are useful in the treatment of ocular inflammation associated with Adamantiades-Behçet's disease, RA, JIA, SpA, Crohn's, sarcoidosis, and Graves' disease ophthalmopathy. Infliximab was also beneficial in small numbers of patients with idiopathic uveitis or scleritis, birdshot retinochoroiditis, uveitic and diabetic cystoid macular edema, and age-related macular degeneration. The currently available data are nonrandomized and thus preliminary, providing the foundation and justification for randomized trials to assess efficacy and safety. Until such results are available, knowledge regarding the use of anti-TNF regimens in ophthalmology is incomplete. However, the preliminary evidence points to a growing optimism for targeting TNF in patients with ocular inflammation.
17106388 Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of dis 2006 Nov Although posttraumatic osteoarthritis (OA) is a common and important entity in orthopedic practice, no data presently exist regarding its prevalence or its relative burden of disease. A population-based estimate was formulated, based on one large institution's experience in terms of its fraction of patients with OA presenting to lower-extremity adult reconstructive clinics with OA of posttraumatic origin. The relative proportion of these patients undergoing total joint replacement provided a basis for extrapolating institutional experience with posttraumatic OA to a populationwide estimate because the numbers of lower-extremity total joint arthroplasty procedures performed were reliably tabulated both within the institution and populationwide. By this methodology, approximately 12% of the overall prevalence of symptomatic OA is attributable to posttraumatic OA of the hip, knee, or ankle. This corresponds to approximately 5.6 million individuals in the United States being affected by posttraumatic OA sufficiently severe to have caused them to present for care by an orthopedic lower-extremity adult reconstructive surgeon. Further, based on the relative prevalence of OA versus rheumatoid arthritis, and their relative impacts as assessed by the SF-36 (Short-Form 36) lower-extremity physical composite scores, about 85.5% of the societal costs of arthritis are attributable to OA. The corresponding aggregate financial burden specifically of posttraumatic OA is Dollars 3.06 billion annually, or approximately 0.15% of the total U.S. health care direct cost outlay.
17038476 IL-32, a novel cytokine with a possible role in disease. 2006 Nov IL-32 is the name given to the NK4 transcript first reported in IL-2 activated T lymphocytes and natural killer cells 13 years ago without known function. The novel cytokine has six isoforms. In an study to isolate a soluble form of the IL-32 receptor from human urine, IL-32alpha bound proteinase-3 with high affinity and was not affected by enzyme inhibition. IL-32alpha/IL-32gamma were expressed as recombinant molecules. The cytokine exhibits properties characteristic of proinflammatory cytokines and also induces the degradation of inhibitory kappaB and phosphorylation of mitogen activated protein p38. Monoclonal antibodies to IL-32 identify its presence in a variety of human tissues from diseases states. Epithelial cells from healthy subjects express low levels of the cytokine, but in disease conditions such as chronic obstructive pulmonary disease, Crohn's disease and psoriasis, the expression increases markedly. IL-32 is a major transcript in gene array studies in epithelial cells stimulated with IFNgamma in vitro. In rheumatoid arthritis, synovial tissues reveals increased content of IL-32, which correlates with severity of disease. A highly significant correlation has been observed between the number of synovial and macrophagic cells positive for IL-32 and the level of erythrocytes sedimentation, IL-1beta, tumour necrosis factor alpha, and IL-18. Thus, IL-32 exhibits many properties of proinflammatory cytokines and associations with disease severity.
16881360 [Clinical associations of C-reactive protein in systemic sclerosis]. 2006 AIM: To evaluate incidence of C-reactive protein (CRP) rise and CRP associations with clinical manifestations in systemic sclerosis (SS). MATERIAL AND METHODS: CRP concentrations in blood serum were estimated with solid phase enzyme immunoassay in 21 SS patients (8 patients with diffuse SS--dSS and 13 patients with limited SS--lSS). Two patients with ISS had documented rheumatoid arthritis (RA)--SS/RA. Forty two healthy donors with normal levels of CRP served control. RESULTS: CRP was elevated in 10 (48%) of 21 SS patients. Mean CRP content was 9.87 +/- 7.73 mg/l (about 3 times higher than in the control group, p < 0.0001) in 20 eligible patients. A mean CRP level did not differ between ISS and dSS patients. RA patients had higher levels of CRP (p = 0.001). CRP was elevated in 4 of 5 (80%) patients with digital ulcers and only in 5 (27%) of 15 patients without ulcers, but the difference was insignificant as well as those in mean CRP in these subgroups. Content of von Willebrand factor antigen (Ag:vW) was high in 7 (33%) patients (mean 1.70 +/- 0.84 IU/ml) this being significantly higher than in the control group (p < 0.0001). CPR concentration closely correlated with that of Ag:vW (r = 0.52; p = 0.017). Close association was found between CRP level and ESR (r = 0.75; p < 0.001) and titer of antinuclear factor (r = 0.52; p = 0.035). CONCLUSION: A moderate rise of CRP level in about 50% cases of SS is associated with arthritis and cutaneous ulcers. A positive correlation between CRP content and Ag:vW in blood suggests that CPB concentrations may reflect severity of vascular damage in SS.
16805955 Oxidative stress parameters in different systemic rheumatic diseases. 2006 Jul The involvement of oxidative stress in the pathogenesis of rheumatic disorders, such as systemic sclerosis (SSc) and chronic polyarthritides, has been suggested yet not thoroughly verified experimentally. We analysed 4 plasmatic parameters of oxidative stress in patients with SSc (n = 17), psoriatic arthritis (PsA) (n = 10) and rheumatoid arthritis (RA) (n = 9) compared with healthy subjects (n = 22). The biomarkers were: total antioxidant capacity (TAC) measured by ferric reducing antioxidant power (FRAP) method, hydroperoxides determined by ferrous ion oxidation in presence of xylenol orange (FOX) method and sulfhydryl and carbonyl groups assessed by spectrophotometric assays. The results showed significantly increased hydroperoxides in SSc, PsA and RA (3.97 +/- 2.25, 4.87 +/- 2.18 and 5.13 +/- 2.36 micromol L(-1), respectively) compared with the control group (2.31 +/- 1.40 micromol L(-1); P < 0.05). Sulfhydryls were significantly lower in SSc (0.466 +/- 0.081 mmol L(-1)), PsA (0.477 +/- 0.059 mmol L(-1)) and RA (0.439 +/- 0.065 mmol L(-1)) compared with the control group (0.547 +/- 0.066 mmol L(-1); P < 0.05). TAC in all three diseases showed no difference in comparison with controls. Carbonyls were significantly higher in RA than in the control group (32.1 +/- 42 vs 2.21 +/- 1.0 nmol (mg protein)(-1); P < 0.05). The obtained data indicate augmented free radical-mediated injury in these rheumatic diseases and suggest a role for the use of antioxidants in prevention and treatment of these pathologies.
18311754 Reliability and validity of the center for epidemiologic studies depression scale in patie 2008 Mar 15 OBJECTIVE: Reported rates of depressive symptoms in patients with systemic sclerosis (SSc) are high. No depression assessment tools, however, have been validated for patients with SSc. Our objective was to assess the internal consistency reliability, convergent validity, and structural/construct validity of the Center for Epidemiologic Studies Depression Scale (CES-D) in patients with SSc. METHODS: We conducted a cross-sectional, multicenter study of 470 SSc patients. Internal consistency reliability was assessed with Cronbach's alpha and structural/construct validity with confirmatory factor analysis. RESULTS: Internal consistency reliability was good for the overall CES-D scale (alpha = 0.88) and for its 4 factors (alpha = 0.67-0.88). Correlations of the CES-D total score were -0.73 with mental health, -0.36 with physical health, 0.41 with disability, and 0.44 with pain. The 4-factor model originally found in the general population and validated for patients with rheumatoid arthritis (depressed affect, somatic/vegetative, [lack of] positive affect, and interpersonal factors) fit the data well, as did a second-order version of the same model with an overarching depression factor that loaded onto each of the 4 first-order factors. The 4-factor model fit the SSc data better than alternative models. CONCLUSION: Internal consistency reliability and convergent validity were good, the 4-factor structure reported in the general population was replicated, and a second-order model with an overarching depression factor fit well. These findings indicate that the CES-D is a valid and reliable measure of depressive symptoms for patients with SSc.
18021510 Quantitative measurement of patient status in the regular care of patients with rheumatic 2007 Nov Patient assessment in rheumatology is characterized by an important paradox: many extensively-characterized quantitative measures and indices have been developed for rheumatoid arthritis (RA), psoriatic arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, vasculitis, osteoarthritis, fibromyalgia, and other rheumatic diseases. However, most regular rheumatology care is guided largely by qualitative clinical impressions, without such measures or indices or any quantitative data other than laboratory tests to assess patient status and/or quality of care. This paradox may be explained in part by regarding the development of measures primarily as clinical research activities, while viewing the application of measurements in regular clinical care as continuous quality improvement (CQI) activities. The development of measures has emphasized validity and reliability, but generally ignored feasibility and acceptability to patients and health professionals, both of which are needed for application in regular clinical care. A summary of the application of clinical measurement in patients with RA over 25 years between 1982 and 2007 at a weekly academic rheumatology clinic conducted by the senior author is presented as 20 often contemporaneous CQI cycles. These cycles include development of a user-friendly modified health assessment questionnaire (MHAQ); assessment of psychological status; monitoring of mortality outcomes; comparisons of joint counts, radiographic scores, and laboratory tests to the MHAQ; a 28-joint count; prospective study of the MHAQ to predict mortality when joint counts, radiographic scores, and laboratory tests are available; development of a multidimensional HAQ (MDHAQ) with complex activities; a fatigue scale; a self-report joint count; scoring templates; a computerized data management system; flow sheets to monitor MDHAQ status; visual analog scales as 21 circles rather than 10 cm lines; composite RAPID3 (rheumatology assessment patient index data) scores for 3 patient measures; and defining RAPID categories for high, moderate and low severity, and near remission. The latter cycles remain under study as ongoing CQI activities.
17297594 Characteristics of patients with systemic lupus erythematosus (SLE) and non-Hodgkin's lymp 2007 Sep Patients with systemic lupus erythematosus (SLE) are at increased risk of developing non-Hodgkin's lymphoma (NHL), but features of SLE associated with NHL are not well described. The objective of this study was to describe SLE characteristics, laboratory serologies, and medication histories in patients who subsequently develop NHL. Two thousand twenty patients with SLE were identified using the online Partners' patient database research tool between October 1992 and June 2005. We confirmed the diagnoses of SLE and NHL and sought details of medical history and treatment by medical record review. Eleven patients with NHL without coexisting rheumatoid arthritis, Sjögren's, or HIV were identified; seven of these (64%) had a diffuse large B cell lymphoma subtype, and 83% of those stained were Epstein-Barr virus (EBV) negative. The mean duration of SLE at NHL diagnosis was 17.8 years (range 1.6-41.8), and the mean Systemic Lupus International Collaborative Clinics/American College of Rheumatology damage index was 1.9. Seven patients (64%) had SLE hematologic involvement, four had anti-dsDNA antibodies, and four had anti-phospholipid antibodies. One patient had significant renal disease. All patients had arthritis and had received antimalarial therapy. Five of 11 patients had received other treatments for SLE, including cyclophosphamide, imuran, methotrexate, and/or sulfasalazine. Diffuse large B cell lymphoma was the most common subtype of NHL, and most were EBV negative. Although disease duration was fairly long and end organ damage moderately severe in this group of patients, renal disease and the use of immunosuppressive chemotherapeutic agents were rare and did not appear to confer an increased risk of NHL development.
17709479 Cutting edge: TNF-alpha-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cell 2007 Sep 1 TNF-alpha, a potent proinflammatory cytokine, is synthesized as a membrane-anchored precursor and proteolytically released from cells. Soluble TNF is the primary mediator of pathologies such as rheumatoid arthritis, Crohn's disease, and endotoxin shock. The TNF-alpha converting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17), has emerged as the best candidate TNF sheddase, but other proteinases can also release TNF. Because TACE-deficient mice die shortly after birth, we generated conditional TACE-deficient mice to address whether TACE is the relevant sheddase for TNF in adult mice. In this study, we report that TACE inactivation in myeloid cells or temporal inactivation at 6 wk offers strong protection from endotoxin shock lethality in mice by preventing increased TNF serum levels. These findings corroborate that TACE is the major endotoxin-stimulated TNF sheddase in mouse myeloid cells in vivo, thereby further validating TACE as a principal target for the treatment of TNF-dependent pathologies.
17520865 Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. 2007 May Intracellular levels of cyclic nuclec tides are closely regulated by distinct families of PD Es, which are responsible for the breakdown and degradation of cyclic nucleotides within cells. Type 4 PDEs have the potency to modulate the release of inflammatory mediators through cAMP-dependent and -independent mechanisms. Selective targeting of PDE4 is currently being investigated as a novel therapeutic approach in the treatment of inflammation-associated respiratory diseases such as asthma and COPD. The development of several PDE4 inhibitors, including roflumilast and cilomilast, reflects the success of this approach. In principle, therapeutic intervention of an inflammatory response by PDE4 inhibitors may be extended to other chronic inflammatory disease states such as psoriasis, rheumatoid arthritis and inflammatory bowel diseases (e.g., Crohns disease and ulcerative colitis). This retiiew explores the feasibility of PDE4 inhibitors as a promising alternative for therapeutic intervention in systemic inflammation and inflammation-based disease.
16884970 Tumor necrosis factor antagonists: different kinetics and/or mechanisms of action may expl 2006 Dec OBJECTIVE: Tumor necrosis factor (TNF) antagonists fall into 2 classes:etanercept (ETA) is a soluble TNF receptor, while infliximab (INF) and adalimumab (ADA) are monoclonal antibodies against TNF. All 3 drugs are effective in treating rheumatoid arthritis. However, these agents have been associated with an increased risk of granulomatous infections, such as tuberculosis and histoplasmosis. Several reports indicate that the incidence of granulomatous infections may potentially be higher in individuals treated with INF than ETA. METHODS: We conducted a comprehensive literature search (1966 to 2004) to review the role of TNF in normal and disease states, and the mechanisms of action of the TNF inhibitors. Specifically, we searched for possible mechanisms for the apparent increase in granulomatous infections associated with TNF inhibitors and for reasons that there may be differences between them. RESULTS: Infection may result from a number of differences between ETA and INF or ADA. First, binding avidities are different, with ETA binding in a 1:1 ratio and INF/ADA binding in 2 to 3:1 ratios. Second, the clearances of ADA, ETA, and INF are different, being about 13 times higher for ETA than INF or ADA, thus resulting in higher steady-state drug levels for ADA and INF. Also, the methods of administration are different, intravenously (for INF) versus subcutaneously (for ETA and ADA), which results in lower peak concentrations for ETA and ADA, potentially explaining some of the differences in effects on granuloma formation. Third, INF and ADA have somewhat different mechanisms of action from ETA: INF and ADA are associated with antibody-mediated cell lysis, while ETA is not; INF may induce apoptosis in some tissues (eg, gastrointestinal [GI] mucosa) while ETA does not--although this is controversial and may not be true at steady state in synovium, where both drugs seem to cause apoptosis; ETA binds lymphotoxin-alpha while INF does not (ETA may thus be more efficient at preventing granuloma formation by this mechanism than INF); finally, ADA and INF seem to inhibit IFN-gamma expression (probably indirectly), while ETA does not. CONCLUSIONS: There are significant differences between the 2 classes of TNF antagonists in terms of both their kinetics and mechanisms of action. These differences may help explain the apparent differences in the incidence of granuloma-dependent infections among them.
16841861 n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. 2006 Jun Inflammation is part of the normal host response to infection and injury. However, excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases and is characterized by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids (prostaglandins, thromboxanes, leukotrienes, and other oxidized derivatives), other inflammatory agents (e.g., reactive oxygen species), and adhesion molecules. At sufficiently high intakes, long-chain n-3 polyunsaturated fatty acids (PUFAs), as found in oily fish and fish oils, decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species and the expression of adhesion molecules. Long-chain n-3 PUFAs act both directly (e.g., by replacing arachidonic acid as an eicosanoid substrate and inhibiting arachidonic acid metabolism) and indirectly (e.g., by altering the expression of inflammatory genes through effects on transcription factor activation). Long-chain n-3 PUFAs also give rise to a family of antiinflammatory mediators termed resolvins. Thus, n-3 PUFAs are potentially potent antiinflammatory agents. As such, they may be of therapeutic use in a variety of acute and chronic inflammatory settings. Evidence of their clinical efficacy is reasonably strong in some settings (e.g., in rheumatoid arthritis) but is weak in others (e.g., in inflammatory bowel diseases and asthma). More, better designed, and larger trials are required to assess the therapeutic potential of long-chain n-3 PUFAs in inflammatory diseases. The precursor n-3 PUFA alpha-linolenic acid does not appear to exert antiinflammatory effects at achievable intakes.
16818966 Revision total knee arthroplasty: 1990 through 2002. A review of the Finnish arthroplasty 2006 Jul BACKGROUND: National and regional arthroplasty registries have been used to study the results of primary total knee arthroplasties. The purpose of this paper was to present the results of revision total knee replacements and describe predictors of survival of those replacements, with repeat revision as the end point. METHODS: The nationwide Finnish Arthroplasty Registry included 2637 revision total knee arthroplasties from 1990 through 2002. Survivorship of the revision total knee arthroplasties was analyzed, with repeat revision as the end point. The survivorship analyses comprised evaluations of the proportional hazards assumption followed by calculations of univariate and multivariate statistics and model diagnostics as appropriate. RESULTS: The survival rate following the revision total knee arthroplasties was 95% (95% confidence interval, 94% to 96%) at two years (1874 knees), 89% (95% confidence interval, 88% to 90%) at five years (944 knees), and 79% (95% confidence interval, 78% to 81%) at ten years (141 knees). Multivariate regression analysis showed the most significant predictors of prosthetic survival to be the age of the patient and the life in service of the primary total knee replacement (that is, the time between the primary total knee replacement and the revision). Survivorship was also significantly predicted by the year of the first revision total knee arthroplasty and the reason for the revision. CONCLUSIONS: An age greater than seventy years, revision five years or more after the primary arthroplasty, and absence of patellar subluxation are positive indicators of survival of a revision total knee replacement. We believe that normal aging as well as the deconditioning effect of disease (osteoarthritis and rheumatoid arthritis) and its treatment (primary total knee replacement) may lead to a reduced activity level, which, together with a presumed reluctance to operate on elderly patients, protects against repeat revisions. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.
16622903 Quality of life and functional status in systemic sclerosis compared to other rheumatic di 2006 Jun OBJECTIVE: To assess clinical factors associated with disability and physical health in patients with systemic sclerosis (SSc) compared to psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) and healthy controls. METHODS: Eighty-two patients with SSc, 82 with PsA, 74 with SLE, 42 with RA, and 60 controls were recruited from various rheumatology clinics and underwent physical examination, tender point count, Health Assessment Questionnaire Disability Index (HAQ-DI) and Short Form-36 Health Survey (SF-36) assessments. RESULTS: SSc patients were younger and had shorter disease duration than the comparator groups. SSc patients with joint involvement had significantly poorer HAQ-DI scores than patients with PsA (1.43 vs 0.84; p < 0.05), and had higher visual analog scale pain scores than RA patients (1.37 vs 1.01; p < 0.05). The SF-36 Physical Component Summary and HAQ-DI score in SSc patients were adversely affected by joint involvement (p < 0.01, p < 0.001, respectively), >or= 11 tender points (p < 0.01, p < 0.001), gastrointestinal (GI) involvement (p < 0.01, p < 0.01), and high skin score (p = 0.02, p < 0.001). CONCLUSION: Physical health relating to quality of life is adversely affected in patients with SSc. Disability is associated with the presence of >or= 11 tender points, a high skin score, and joint and GI involvement. Joint involvement in SSc is more disabling than joint involvement in PsA; and patients with SSc experience more severe pain than patients with RA.