Dyslipoproteinaemia in a subset of patients with rheumatoid arthritis.
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Aged↗
Biomedical subjects
A Kavanaugh
Publications and source records attributed to A Kavanaugh.
Evaluation of patients with suspected immunodeficiency.
Immunodeficiency diseases represent quantitative or qualitative defects in the normal immune response. Immunodeficiency should be suspected in patients who have recurrent or complicated infections. Conditions associated with secondary immunodeficiency should be ruled out by the history and physical examination, supplemented by routine laboratory tests. Functional analysis of the humoral, cell-mediated and phagocytic aspects of the immune system will reveal most immunodeficiency states. The therapeutic approach includes evaluation and treatment of all infections and, if possible, treatment of the immunologic defect.
Diagnosis, Differential↗
Medicine is becoming just another job.
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Career Choice↗
Alterations in immune function in rats caused by dietary lipotrope deficiency: effect of age.
Weanling male Sprague-Dawley rats were maintained on a control (C), folacin-deficient (F) or marginal methionine-choline diet (M/C) for 3 weeks, 3 months or 12 months. The immunocompetence of the animals was determined by in vivo (response to infection with salmonella typhimurium) and in vitro (lymphocyte transformation assay) methods. It was found that young animals were most sensitive to dietary lipotrope deficiency, and the in vivo response to bacterial infection did not always correlate with in vitro assessment of immune function. Histopathologic examination of spleens from S. typhimurium-infected rats maintained for 3 weeks on the experimental diets showed an overall decreased cellularity especially in the follicular areas, compared to controls. No differences were seen in the spleens of infected animals at later time points. A short-term (3-week) lipotrope deficiency resulted in a depressed lymphocyte transformation response to concanavalin A (Con A) in the spleen, thymus and lymph nodes; to phytohemagglutinin A (PHA) in the spleen and lymph nodes only. After 3 months on the F or M/C diets, a depressed Con A-induced transformation response was still seen in the spleen, but the normal aging-induced immunosuppression resulted in a low response in all animals, with few significant differences existing among groups.
Aging↗
An overview of immunomodulatory intervention in rheumatoid arthritis.
In recent years there has been exceptional progress in the development of immunomodulatory interventions for the treatment of rheumatoid arthritis (RA). Part of the impetus for the creation of novel therapies for RA has come from a growing appreciation of the substantial morbidity and mortality that this chronic, progressive disease causes for affected patients. In addition, there has been the realization that currently available therapeutics are suboptimal as regards both their efficacy and tolerability. The development of newer therapies has been facilitated by two factors; a greater understanding of the immunopathogenesis of RA and progress in biotechnology that has allowed the creation of specific inhibitors and other agents. Myriad studies performed by investigators throughout the world have helped delineate the immunologic basis of RA. It appears that various components of the immune system are involved in the initiation and propagation of this systemic inflammatory disease. T-cells, and in particular activated CD4(+) 'memory' T-cells, serve a central role in orchestrating the immune response that underlies rheumatoid inflammation. Other cells, including monocytes, fibroblasts, B-cells, dendritic cells, mast cells and neutrophils also contribute significantly to various aspects of disease. Adhesion molecules mediate many intercellular interactions, thus contributing to activities such as the accrual of cells within the synovium and the activation of cells. Cytokines, small peptides that exert numerous inflammatory activities and cause many of the signs and symptoms of RA, play a crucial role. Indeed, RA may be considered a disorder of 'cytokine dysregulation' in that the activity of proinflammatory cytokines such as TNF-alpha and IL-1 is enhanced, and overwhelms the effects of antiinflammatory factors. Finally, a host of other inflammatory mediators are involved in the disease process. Thus, many components of the immune response may be attractive therapeutic targets for immunomodulatory intervention in RA. Advances in biotechnology have permitted the creation of specific inhibitors of distinct components of the immune system. Monoclonal antibodies (MAbs) have been created to target various cell surface molecules and cytokines. At first, most MAbs were murine in origin, which can present problems as regards immunogenicity. More recently, progress in molecular biologic techniques has allowed the synthesis of hybrid antibodies that are partly human. Such techniques have also allowed the creation of cytokine receptors coupled to immunoglobulin molecules, and other constructs. These agents can be modified to provide optimal characteristics in terms of half-life, immunogenicity and specificity, and this is an exciting area of new development. Progress has also been made in molecular-based agents that directly modify the genes or gene products for specific targets. To date, a number of trials assessing novel immunomodulatory therapies have been undertaken. In some cases, such as with inhibitors of TNF-alpha, the results have been dramatic and exciting. Further development and refinement may allow the introduction of these agents into the clinic in the foreseeable future, and will provide an important area for further research. In other cases, for example with therapies targeting CD4(+) molecules, the results have not been as promising as was hoped. Nevertheless, critical analysis of the results of these studies has provided insights into the pathogenesis of RA which may prove quite valuable for future trials. A number of agents are being studied actively at the present time, and it is hoped that they too may generate novel therapies for, and a greater understanding of, this difficult disease. The future for immunomodulatory intervention in RA looks very promising. Greater understanding of the intricacies of the immune response that underlie this disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. This should allow the clinician truly to modify the disease and achieve tangible improvements in the lives of RA patients.
Journal Article↗
Anti-TNF therapy for other inflammatory conditions.
The use of biological agents in inflammatory conditions is rapidly increasing. TNFalpha blocking treatments have changed the course of rheumatoid arthritis, Crohn's disease, juvenile rheumatoid arthritis and psoriatic arthritis. Open label studies with TNFalpha inhibitors in other inflammatory conditions such as adult Still's disease, uveitis, Wegener's granulomatosis, Behçet's disease, scleroderma, Sjögren's syndrome, sarcoidosis, pyoderma gangrenosum, polymyositis/dermatomyositis have shown promising results. However, whether anti-TNFalpha therapy can be safely and efficaciously applied to these other inflammatory disorders requires further controlled studies.
Antibodies, Monoclonal↗
Discussion. Section 2: immunomodulatory intervention.
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Journal Article↗
The safety of biologic agents in early rheumatoid arthritis.
Accompanying the excitement surrounding the prominent efficacy of biologic agents in rheumatoid arthritis (RA) has been concern regarding potential adverse effects. Data from clinical trials and pharmacovigilance has provided an assessment of their safety in patients with established RA. As biologic agents are utilized in patients with earlier disease, optimal determination of the risk/benefit will depend on continued careful monitoring, collection, reporting and analysis of safety information.
Adalimumab↗
Benefit/risk of therapies for rheumatoid arthritis: underestimation of the "side effects" or risks of RA leads to underestimation of the benefit/risk of therapies.
Most physicians are familiar with the side effects or risks of drugs used to treat rheumatoid arthritis (RA), but relatively less familiar with the "side effects" or risks associated with RA itself RA is not thought to have the same potential severity as a cardiovascular or neoplastic disease by most physicians, the public, or even some rheumatologists, although relative rates of predicted mortality in some patients with RA are in the range of some people with coronary artery disease or Hodgkin's disease. Many reasons may be identified to explain why the risks of RA have been underestimated: RA does not lead to acute life-threatening situations; population-based data have suggested that most people who meet criteria for RA have a mild or self-limited process; acute attributed causes of death in people with RA are superficially similar to those in the general population; clinical trials have suggested many therapies that are efficacious over a period of 3-12 months; few long-term longitudinal studies were performed prior to the 1980s; medical recommendations made during the 1950s-1980s suggested that simple therapies were adequate for most patients; and quantitative information concerning patient status is generally not included in standard rheumatology care. As more information has emerged concerning severe long-term outcomes in the "natural history" of RA (as treated prior to the 1990s), new strategies of aggressive intervention have been developed. Furthermore, basic research has led to new therapies. It appears that the benefit/risk ratio of therapies for RA has increased substantially over the last two decades, and the outlook for patients with RA is much better at this time than in previous years.
Antirheumatic Agents↗
Quantitative documentation of benefit/risk of new therapies for rheumatoid arthritis: patient questionnaires as an optimal measure in standard care.
Assessment of benefit/risk of therapies for any disease is best conducted according to quantitative data. In many diseases, such as hypertension or hyperlipidemia, a single quantitative measure serves as a "gold standard" for patient status, but no single measure can serve as a "gold standard' for all individual patients with rheumatoid arthritis (RA). Therefore, indices such as the American College of Rheumatology (ACR) Core Data Set and Disease Activity Score (DAS), are used in clinical trials and other clinical research. These indices include 3 types of measures, which are derived from a health professional [joint counts, global]; a laboratory [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]; or a patient questionnaire [physical function, pain, global]. In most standard clinical care, the majority of clinicians do not collect joint count or patient questionnaire data at most visits. Therefore, assessment and management of most patients with RA is conducted empirically, with the only quantitative data from laboratory tests. Measures on a patient self-report questionnaire of physical function, pain, and global status, are as informative as joint counts, radiographic scores, laboratory tests, or any measure by a health professional to document status, estimate prognosis, and monitor responses to therapies. We suggest that quantitative measurement may be incorporated into standard clinical care most easily and effectively by asking each patient to complete a simple 1-page questionnaire at each visit to a rheumatologist.
Antirheumatic Agents↗
Internet-based monitoring of patients with rheumatoid arthritis.
Patient-derived measures have been increasingly recognized as a valuable means for monitoirng patients with rheumatoid arthritis. One advantage of this data is that it can be collected remotely. This would allow more frequent and more rapid assessments, which could optimize therapeutic intervention and patient outcome.
Adult↗
Relative versus absolute goals of therapies for RA: ACR 20 or ACR 50 responses versus target values for "near remission" of DAS or single measures.
Therapies for rheumatoid arthritis (RA) may be assessed according to relative levels of measures to compare efficacy to another therapy or to a placebo, as in the American College of Rheumatology (ACR) 20%, 50%, or 70% (ACR 20 ACR 50 and ACR 70) responses, or by absolute levels of measures, as in disease activity scores (DAS), ACR criteria for remission, or "target values" of specific measures. Regulatory considerations have emphasized primarily relative comparisons to a placebo or standard therapy, derived in part from the weak efficacy of traditional disease modifying anti-rheumatic drugs (DMARDs). While improvement compared to placebo certainly indicates efficacy, it is of concern that measures of inflammatory activity, such as swollen joints and the erythrocyte sedimentation rate (ESR), may be stable or improved over periods of 5-10 years, while measures of damage, such as joint deformity and radiographic changes, may progress over the same period in the same patients. These findings suggest that improvement at a level of 20% or 50% may deter but not prevent severe long-term outcomes of radiographic progression, functional declines, work disability, and premature mortality, seen in most patients until the middle 1990s. Outcomes appear to be improved at this time, associated with aggressive treatment strategies and more powerful therapies, including biologic agents. In the Finnish Rheumatoid Arthritis Combination Therapy Trial (FinRACo), no patient who was in remission after 6 months was receiving work disability payments 4 1/2 years later, compared to 22% of patients who had ACR 20 or 50 responses and 54% of patients who did not have ACR 20 responses after 6 months who were all receiving work disability payments after 5 years. These findings suggest that absolute targets, including remission, may be realistic contemporary goals, with aggressive treatment strategies and more effective DMARDs and biologic agents.
Antirheumatic Agents↗
Tuberculosis and opportunistic infections: relevance to biologic agents.
With the expanding use of biologic agents, in particular TNF inhibitors, tuberculosis and other opportunistic infections have become an important and growing concern in rheumatology. Clinicians using these therapies should have an understanding of the scope of the problem, the underlying scientific rationale, as well as the optimal approaches to screening, monitoring and treatment.
Animals↗
The use of second generation anti-CCP antibody (anti-CCP2) testing in rheumatoid arthritis--a systematic review.
OBJECTIVE: To evaluate the diagnostic properties and predictive value of the second generation of anti-CCP antibodies (anti-CCP2) in rheumatoid arthritis (RA) patients. METHODS: A systematic review of the published literature between January 2002 and June 2005 was performed. Data were extracted regarding the sensitivity and specificity of anti-CCP2 antibodies in making an accurate diagnosis of RA, predicting future development of RA, and predicting future radiological damage in RA patients. In addition, the prevalence of CCP2 antibodies in patients with other rheumatic diseases was examined. RESULTS: Among 38 studies initially identified, 27 provided information on the use of anti-CCP2 testing. Diagnostic properties were assessed in 13 studies; reported sensitivities ranged from 14.4% to 96%, and specificities from 88.9% to 100%. Odds ratios (OR) for the future development of RA varied from 15.9 among previously healthy individuals to 37.8 among a group of patients with undifferentiated arthritis. Several studies suggested that the presence of anti-CCP2 antibodies is highly predictive of current radiographic damage and further damage progression. CONCLUSIONS: Anti-CCP2 has a low sensitivity to be used as a screening test. However, a positive test is highly specific for RA. In addition, anti-CCP2 appears to be highly predictive of the future development of RA in both normal individuals and patients with undifferentiated arthritis. Finally, the presence of anti-CCP2 antibodies appears to predict radiographic damage and progression among patients with RA.
Arthritis, Rheumatoid↗
The assessment of disease activity and outcomes in psoriatic arthritis.
Psoriatic Arthritis (PsA) is a common condition that significantly impacts affected patients. The introduction of novel therapeutic agents for PsA has generated considerable interest in both clinical trials and in clinical care. Thus, there is a great need for standardized outcome measures to assess the activity of disease and the response to therapy. Because psoriasis is a heterogeneous and multi-faceted condition, defining outcome measures has been a challenge. To date, such measures have largely been adapted from related diseases, as described in this essay. Further research is needed to further develop outcome measures for PsA to facilitate optimal treatment of patients with PsA.
Arthritis, Psoriatic↗
Complexities in defining remission in rheumatic diseases.
The rheumatology community has devoted increasing attention to the subject of remission over the past 2 decades, on the basis of greater appreciation of the long-term severity of inflammatory rheumatic diseases and availability of new therapies and approaches to improve outcomes. Nonetheless, description of remission in rheumatic diseases is complex, compared to many nonrheumatic diseases. Recognition of remission requires a set of measures or an index rather than a single "gold standard." Spontaneous remission is not infrequent in people with early inflammatory arthritis, including some who may meet criteria for rheumatoid arthritis (RA) over less than a few months, and may be confused with a drug-induced remission. Remission may be transient in many patients over short periods, and the length of time required to maintain remission status varies in different reports. Maintenance of a state of remission in autoimmune diseases that result from dysregulatory processes, rather than invasion of foreign cells or toxins, generally requires ongoing therapy indefinitely. Patients who have organ damage or functional disability may be described as "in remission," although they are free of disease activity only, but not necessarily free of disease consequences. A status of "low disease activity" or "near remission" with 70% to 90% of the features of an ideal remission may be adequate for many people with rheumatic diseases to avoid risks that may be required to reach 100% remission status. Thus, the subject of remission remains under active discussion in the rheumatology community.
Antirheumatic Agents↗