Rheumatoid Arthritis: Alberta

Zordoky BN, El-Kadi AO. · Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8. · Curr Drug Metab. · Pubmed #19275551 No free full text.

Abstract: Nuclear factor kappa B (NF-kappaB) is an important transcription factor that regulates a wide spectrum of genes including cytochrome P450 (CYP), the most important family of drug metabolizing enzymes. Therefore, in this review, we addressed the potential role of NF-kappaB in CYP regulation. We proposed three mechanisms by which NF-kappaB can regulate CYP expression and activity. First, NF-kappaB can directly regulate the expression of CYP1A1, CYP2B1/2, CYP2C11, CYP2D5, CYP2E1, CYP3A7, and CYP27B1 through binding to the promoter region of these genes. Second, NF-kappaB indirectly regulates the transcription of CYP genes through mutual repression with some nuclear receptors that are involved in CYP regulation such as AhR, CAR, GR, PXR, RXR, PPAR, FXR, and LXR. Finally, NF-kappaB can regulate CYP activity at post-transcriptional level by inducing heme oxygenase or by affecting the CYP protein stability. In addition, increased inflammatory mediators, oxidative stress, and subsequent NF-kappaB activation have been demonstrated in many conditions such as inflammatory bowel diseases, rheumatoid arthritis, psychological stress, diabetes, aging, cancer, renal diseases, and congestive heart failure. Meanwhile, there is a significant alteration of CYP expression and activity in these diseases. Therefore, we propose that NF-kappaB could be one of the links between inflammation, oxidative stress, and CYP regulation in these diseases. In conclusion, NF-kappaB plays a crucial role in the regulation of CYP through several mechanisms and this role can explain the altered CYP regulation in many conditions.

Hirota SA, Beck PL, MacDonald JA. · Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada. · Recent Pat Inflamm Allergy Drug Discov. · Pubmed #19149741 No free full text.

Abstract: In response to hypoxia, adaptive hypoxia-inducible factor-1 (HIF-1) signaling events are activated to increase oxygen transport, anaerobic energy production and protective pathways to minimize ischemic tissue damage. Although the activation and subsequent induction of gene transcription by HIF-1 is normally associated with hypoxia, it is now established that HIF-1 signaling can be triggered under inflammatory conditions. HIF-1 has been implicated in a number of inflammatory diseases including rheumatoid arthritis, allergic asthma, psoriasis and inflammatory bowel disease (IBD). In the gastrointestinal tract, HIF-1-regulated gene products, such as vascular endothelial growth factor, intestinal trefoil factor and CD73, have been shown to provide protection in animal models of intestinal inflammation. Given the importance of HIF-1 signaling in the aforementioned diseases, there exists considerable interest in the development of methods to modulate HIF-1 expression as well as down-stream signaling events. This review examines HIF-1 signaling with a special focus on the gastrointestinal tract. The patents pertaining to the modulation of HIF-1 signaling are summarized, and their relevance to the treatment of inflammatory bowel disease is discussed.

Keeling SO, Oswald AE. · Division of Rheumatology, Department of Medicine, University of Alberta, 562 Heritage Medical Research Center, Edmonton, Alberta, Canada. · Clin Rheumatol. · Pubmed #18987777 No free full text.

Abstract: Pregnancy is an important condition that can affect and be affected by rheumatic disease. Overall, pregnancy is viewed as a Th2-predominant state, but several Th1-related cytokines are vital to early pregnancy. In rheumatoid arthritis for example, the majority of women improve by the beginning of the second trimester, but the majority (90%) will flare in the first 3 to 4 months postpartum. In contrast, systemic lupus erythematosus has an unpredictable course in pregnancy, leaving most rheumatologists to recommend a disease-quiescent state prior to conception. Other diseases such as scleroderma are less clear because the disease less commonly presents in the childbearing period. Many immunosuppressive medications for the rheumatic diseases are contraindicated in pregnancy because of their mechanisms of action leaving only a select few "safe" medications. Significant heterogeneity between the Food and Drug Administration (FDA) category for a medication and what a rheumatologist does in clinic leads to confusion on how a patient should be treated for active rheumatic disease both peripartum and postpartum, particularly if the patient is breastfeeding. We review the general state of pregnancy and how it is affected by prototypical rheumatic diseases including rheumatoid arthritis and systemic lupus erythematosus. In addition, we present the most commonly used disease-modifying antirheumatic drugs and immunosuppressants and explain the difference between the FDA category and clinical practice among rheumatologists. Finally, we provide some general recommendations on how to manage a rheumatic disease during pregnancy including: (a) preconception planning to ensure no teratogenic medications on board, (b) early disclosure of pregnancy to all caregivers including the rheumatologist, family physician, obstetrician, and maternal-fetal medicine specialist, and (c) planning of safe medication use for acute flare-ups and disease suppression peripartum and postpartum.

Russell AS. · Rheumatic Disease Unit, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada. · Pharmacoeconomics. · Pubmed #18793031 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic and lifelong autoimmune disorder that results in significant pain, disability and excess mortality if untreated or inadequately treated. Quality-of-life (QOL) assessments are particularly important in the absence of a cure for RA. Generic and disease-specific patient-reported QOL instruments, such as the Health Assessment Questionnaire (HAQ) Disability Index and the SF-36, have proven validity and sensitivity for assessment of changes in QOL in clinical trials of disease-modifying anti-rheumatic drugs (DMARDs). However, these instruments are rarely utilized in clinical practice, and patients have reported that the actual clinical assessments alone do not address important parameters, such as fatigue and disturbed sleep, which significantly affect QOL.New biological DMARDs have shown significant efficacy in improving clinical and QOL parameters in randomized controlled trials. However, the high cost of biological DMARDs compared with non-biological DMARDs is a factor in the increasing health costs associated with the treatment of RA. Generic health utility instruments that measure QOL parameters enable calculation of the increased QALYs associated with more costly treatment in patients with RA. The costs per QALY associated with biological DMARDs in RA appear to be comparable to those of other accepted medical interventions. Interest in incorporating QOL parameters in formulary and public health decision making concerning the use of new agents for RA is increasing.

Stinton LM, Fritzler MJ. · Department of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1. · Autoimmun Rev. · Pubmed #17967730 No free full text.

Abstract: Musculoskeletal (MSK) disorders constitute one of the most common clinical presentations to clinical care givers. Within this category of illnesses, systemic autoimmune rheumatic diseases (SARD) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SjS) and rheumatoid arthritis (RA) are included in the differential diagnosis. A hallmark of SARD is the production of autoantibodies, which are routinely requested as a guide to diagnosis and clinical decision making. The field of serological tests, including the detection of autoantibodies, is complex and often leads to confusion and misunderstanding. When used appropriately, autoantibodies can be a valuable adjunct to the diagnosis, and occasionally therapy and prognosis, of SARD. The role of autoantibody testing and a 'practical' approach to using these tests is the focus of this paper.

Jones JL, Loftus EV. · Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada. · Inflamm Bowel Dis. · Pubmed #17600819 links to  free full text

Abstract: With the increasingly widespread use of immunosuppressive and biologic agents for the treatment of Crohn's disease and ulcerative colitis come concerns about potential long-term consequences of such therapies. Disentangling the potential confounding effects of the underlying disease, its extent, severity, duration, and behavior, and concomitant medical therapy has proven to be exceedingly difficult. Unlike the case in rheumatoid arthritis, the overwhelming preponderance of population-based evidence suggests that a diagnosis of inflammatory bowel disease (IBD) is not associated with an increased relative risk of lymphoma. However, well-designed studies that evaluate the potential modifying effect of IBD severity have yet to be performed. Although the results from hospital- and population-based studies have conflicted, the results of a recent meta-analysis suggest that patients receiving purine analogs for the treatment of IBD have a lymphoma risk approximately 4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against tumor necrosis factor-alpha are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, there may be a small but real risk of lymphoma associated with these therapies. Although the relative risk of lymphoma may be elevated in association with some of the medical therapies used in the treatment of IBD, this absolute risk is low. Weighing the potential risk of lymphoma associated with select medical therapies against the risk of undertreating IBD will help physicians and patients to make more informed decisions pertaining to the medical management of IBD.

Keeling SO, Landewe R, van der Heijde D, Bathon J, Boers M, Garnero P, Geusens P, El-Gabalawy H, Inman RD, Kraus VB, Kvien TK, Mease PJ, Ostergaard M, Ritchlin C, Syversen SW, Maksymowych WP. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · J Rheumatol. · Pubmed #17343310 No free full text.

Abstract: OBJECTIVE: A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker extensively studied in RA, was then used to test these criteria. Our objectives were: (1) To assess the strength of evidence in support of CRP as a soluble biomarker reflecting structural damage in RA according to the draft validation criteria. (2) To assess the strength of recommendation for inclusion of individual criteria in the draft set. METHODS: A systematic literature review was conducted to elicit evidence in support of each specific criterion composing the 14-criteria draft set. A summary of the key literature findings per criterion was presented to both the working group and to participants in a special interest soluble biomarker group at OMERACT 8. Participants at OMERACT 8 were asked to rate the strength of evidence and the strength of the recommendation in support of each individual criterion on a 0-10 numerical rating scale. Working group members not present at OMERACT voted by a Web-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (< 7) for CRP as a biomarker reflecting structural damage in RA; this was true for all criteria except those listed under the category of feasibility and 2 listed under the category of discrimination pertaining to assay reproducibility and evidence regarding sources of variability. Ratings for strength of recommendation for inclusion of each of the 14 criteria in the draft set were high (> 7) except for those criteria listed under the category of truth. CONCLUSION: The draft criteria serve as a useful template in the evaluation of the strength of evidence in support of a particular soluble biomarker as reflecting structural damage in RA.

Giembycz MA, Smith SJ. · Department of Pharmacology and Therapeutics, Respiratory Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · Curr Pharm Des. · Pubmed #17020529 No free full text.

Abstract: Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.

Ajuebor MN, Carey JA, Swain MG. · Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada. · J Immunol. · Pubmed #16887960 links to  free full text

Abstract: The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.

Dagenais NJ, Jamali F. · Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. · Pharmacotherapy. · Pubmed #16164395 No free full text.

Abstract: Angiotensin II, the major effector molecule produced from the renin-angiotensin-aldosterone axis, is a vasoconstrictor contributing to hypertension. Evidence indicates, however, that angiotensin II also is a potent proinflammatory mediator with growth and remodeling effects. In vitro and in vivo studies have shown that angiotensin II blockade significantly reduces concentrations of proinflammatory mediators and oxidative stress products in numerous inflammatory models. Interruption of angiotensin II activity with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been beneficial for patients with inflammatory diseases. Much of this benefit occurs independent of the antihypertensive effect of angiotensin II interruption, suggesting a distinctive protective mechanism. Angiotensin II receptor blockers may represent a novel class of antiinflammatory drugs with indications far beyond cardiovascular diseases.

Norman MU, Hickey MJ. · Immunology Research Group, University of Calgary, Calgary, AB, Canada. · Tissue Antigens. · Pubmed #16101827 No free full text.

Abstract: The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naïve lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.

Maksymowych WP. · Alberta Heritage Foundation for Medical Research, University of Alberta, 562 Heritage Medical Research Building, Edmonton, Alberta T6G 2S2, Canada. · Curr Rheumatol Rep. · Pubmed #15918993 No free full text.

Abstract: Recent interest in therapeutic developments for ankylosing spondylitis has focused primarily on two anti-tumor necrosis factor-a therapies, infliximab and etanercept, with several reports establishing their efficacy in pivotal phase III trials. Open extension analyses of earlier controlled trials have also shown that efficacy is maintained for at least 3 years, that monotherapy is adequate, and that treatment is well tolerated with few serious infections. Treatment is associated with reduction in sick leave and days spent in hospital. Despite induction of antinuclear antibodies and anti-ds DNA antibodies, clinical sequelae are rare. Reduction in magnetic resonance imaging parameters of inflammation and serologic biomarkers of cartilage turnover suggest that these agents may be disease-modifying though direct evidence from plain radiographic studies is still lacking. Conventional second line therapies typically used in rheumatoid arthritis have also been examined and while leflunomide appears to possess limited efficacy, there may be a case for re-examining the value of methotrexate.

Ting PT, Barankin B. · University of Calgary, Alberta. · Can Fam Physician. · Pubmed #15732219 links to  free full text

This publication has no abstract.

Barr SG, Martin L, Chung C, Maksymowych WP. · Department of Medicine, University of Calgary, Canada. · Clin Exp Rheumatol. · Pubmed #15552513 No free full text.

Abstract: Regulatory authorities in Canada have expressed a vital need for pharmacoepidemiological data on long-term effectiveness, safety, and cost-benefit of new therapies, particularly in comparison to currently available therapies, in routine clinical practice to allow informed decision making in listing new therapies on formulary. We describe the evolution of a new model of pharmacosurveillance involving a partnership between academic and community rheumatologists, government, and industry whereby access to therapy is conditional on participation in an industry-funded pharmacosurveillance study that assesses long-term effectiveness, safety, and cost-benefit. Though funded by industry, the program is administered by government and designed and operated at arms length from industry. The clinic data sheets are available at www. altarheum.com. The program also provides a sustainable model for promoting observational research on therapeutics in general.

Homik JE, Suarez-Almazor M. · 562 Heritage Medical Research Centre, University of Alberta, Edmonton, Alta. T6G 2S2, Canada. · Best Pract Res Clin Rheumatol. · Pubmed #15121040 No free full text.

Abstract: Economic analyses have the potential to put all of the positive and negative outcomes of an intervention into perspective to aid decision making. The quality of the data upon which the analysis is based has an impact on the resulting quality of the analysis itself. Analysis of cost-effectiveness requires the input of many types of data, and where data are not available, assumptions must be made. There are many instances where the analysis may go wrong, and it is important to remain cognizant of these. The critical parts of the analysis, which have also been identified in quality assessment tools, include the following: design of the study question, sources of probability estimates and cost data, sensitivity analysis, and the interpretation of results. If the readers are able to identify the assumptions of the analysis they are better equipped to judge the validity. We have reviewed economic analyses relating to two hot economic topics in rheumatology. These are the cost-effectiveness of cyclooxygenase-2 (COX-2) inhibitors for 'arthritis' and cost-effectiveness of anti-tumor necrosis factor alpha (anti-TNF) agents for rheumatoid arthritis (RA). The results of the COX-2 analyses vary by review. Some show cost savings, while others calculate a significant cost in order to achieve any change in quality of life. Given the unanswered questions that still exist, it seems reasonable to conclude that COX-2 inhibitors may be cost effective when used in patients at a high risk of GI complications. Unanswered questions remain regarding the concomitant use of low-dose ASA and proton pump inhibitors and how they may affect the results of these economic analyses. The cost-effectiveness of anti-TNF agents has not been explored in as much detail as that of the COX-2 agents. Two studies have presented cost-effectiveness models that include a hypothetical biologic agent. Two economic analyses report on the cost-effectiveness of etanercept compared with traditional disease-modifying anti-rheumatic drugs (DMARDs) in methotrexate-resistant and methotrexate-naïve patients with RA. Both the analyses show that etanercept has a cost-effectiveness ratio of around 40,000 US dollars for every patient who achieves an American College of Rheumatology 20% improvement score (ACR 20) within a 6-month period. A cost-utility analysis was published regarding the use of infliximab in methotrexate resistant RA. It showed a cost-utility ratio of 3400:34,000 Euro per quality adjusted life year (QALY) gained, depending on the country evaluated (Sweden and the UK, respectively). An important finding in all three studies was that indirect costs dominate costs in RA; therefore, they should be included in all future analyses of this disease.

Hart DA, Kydd AS, Frank CB, Hildebrand KA. · Department of Surgery, McCaig Centre for Joint Injury and Arthritis Research, University of Calagary, 3330 Hospital Drive NW, Calgary, Alta., Canada T2N 4N1. · Best Pract Res Clin Rheumatol. · Pubmed #15121039 No free full text.

Abstract: Rheumatoid arthritis (RA) is a systemic inflammatory disease that can elicit a variable disease course, can influence a variable number of joints, and can exhibit a variable response to treatment. All of these factors contribute to the degree and extent of damage to joint components, as well as the potential for repair of other injured joint tissues/components. Furthermore, some of the RA treatments/drugs themselves can influence repair and injury responses, as well as the outcome of surgical interventions for advanced disease. However, as treatments and interventions become more sophisticated and successful in patient populations, the opportunity to initiate the repair/replacement of the damaged joint tissues also becomes more of a reality. This review will address the current clinical findings in the literature, and then discuss the issues and opportunities to initiate repair of damaged or injured joint tissues in order to restore joint function. These include growth factors, gene therapy, and bioengineered tissues, alone or in combination to augment endogenous repair or replace tissue damaged beyond such repair capabilities.

Maksymowych WP. · Department of Medicine, University of Alberta, Edmonton. · Can Fam Physician. · Pubmed #15000337 links to  free full text

Abstract: OBJECTIVE: To review recent developments in diagnosis and treatment of ankylosing spondylitis (AS). QUALITY OF EVIDENCE: Level I evidence from three randomized placebo-controlled trials shows that AS is highly responsive to anti-tumour necrosis factor-alpha (anti-TNFalpha) therapies when the standard approach of nonsteroidal anti-inflammatory drugs (NSAIDs) and physical modalities fails. MAIN MESSAGE: Ankylosing spondylitis is associated with disability comparable to that of rheumatoid arthritis. Diagnosis should first focus on eliciting a history of nocturnal back pain, diurnal variation in symptoms with prolonged morning stiffness, and a good response to NSAID therapy. Physical examination is often unrevealing. Pelvic x-ray results are often normal in early disease. Magnetic resonance imaging is the most sensitive imaging technique for detecting early inflammatory lesions and should be considered when history supports the diagnosis but results of plain radiography are normal. When patients have failed at least two courses of NSAID therapy, anti-TNF(alpha)therapies are of proven benefit. CONCLUSION: New magnetic resonance imaging techniques and highly effective therapies make AS more readily detectable and managable.

Rankin JA. · University of Calgary, Faculty of Nursing, Calgary, Alberta, Canada. · AACN Clin Issues. · Pubmed #14767362 No free full text.

Abstract: Inflammation may be defined as the normal response of living tissue to injury or infection. It is important to emphasize two components of this definition. First, that inflammation is a normal response and, as such, is expected to occur when tissue is damaged. Indeed, if injured tissue did not exhibit signs of inflammation this would be considered abnormal. Secondly, inflammation occurs in living tissue, hence the need for an adequate blood supply to the tissues in order for an inflammatory response to be exhibited.The inflammatory response may be triggered by mechanical injury, chemical toxins, invasion by microorganisms, and hypersensitivity reactions. Three major events occur during the inflammatory response: the blood supply to the affected area is increased substantially, capillary permeability is increased, and leucocytes migrate from the capillary vessels into the surrounding interstitial spaces to the site of inflammation or injury.The inflammatory response represents a complex biological and biochemical process involving cells of the immune system and a plethora of biological mediators. Cell-to-cell communication molecules known collectively as cytokines play an extremely important role in mediating the process of inflammation. An extensive exposition of this complex phenomenon is beyond the scope of this article. Rather, the author provides a review of inflammation, an overview of the role of certain biological mediators in inflammation, and a discussion of the implications of certain biological response modifiers in clinical practice.

Maksymowych WP, Inman RD, Gladman D, Thomson G, Stone M, Karsh J, Russell AS, Anonymous00134. · The University of Alberta, Edmonton, Canada. · J Rheumatol. · Pubmed #12784417 No free full text.

Abstract: Spondyloarthritis (SpA) represents a group of related arthritides characterized by their association with HLA-B27 and the development of sacroiliitis and enthesitis. Functional impairment, disability, and loss of quality of life may resemble that observed in rheumatoid arthritis. The SpA Research Consortium of Canada (SPARCC) is an informal association of rheumatologist members of the Canadian Rheumatology Association (CRA) with a special interest in therapeutics and outcomes research in SpA. Recent experience with anti-tumor necrosis factor-a (anti-TNF-a) directed therapies prompted a consensus-based evaluation of the evidence supporting their efficacy, safety, and appropriate use in SpA. We evaluated the clinical evidence in support of anti-TNF-a directed therapies in SpA. Medline was searched using appropriate keywords. Abstracts of the 1999-2002 annual meetings of the American College of Rheumatology and the European Congress of Rheumatology were extracted and admitted if sufficient detail was available to determine the level of evidence. Recommendations were based on randomized placebo-controlled trials (Level A evidence) and clinical studies without randomization (Level B evidence). Where the scientific literature was incomplete, recommendations reflected the consensus of SPARCC members (Level C evidence). Following development of an original draft document, consensus for revisions was achieved among members of SPARCC. The document was then posted on the CRA website prior to its final revision. The following recommendations have been endorsed by the Therapeutics Committee of the CRA: Infliximab and etanercept are indicated for reduction of signs and symptoms of moderate to severely active SpA in patients who have had an inadequate response to maximal doses of > or = 2 nonsteroidal antiinflammatory drugs (NSAID) over a 3-month period of observation; and either sulfasalazine or methotrexate is indicated in those with predominantly active peripheral arthritis. Current evidence supports their use as monotherapy (level of evidence A) for at least one year. NSAID and/or second line therapy with either sulfasalazine or methotrexate can be continued concomitantly. There is no evidence addressing potential advantages or disadvantages of combining methotrexate with anti-TNF therapy for SpA. Recommended doses for adults are: infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter; etanercept 25 mg subcutaneously twice weekly. No therapy has been shown to slow progression of axial disease in SpA, and prognostic factors for determining response to therapy remain to be determined. It is the position of the CRA that all therapeutic options should be equally available according to the best judgments of the treating physician and the informed decision of the patient.

Krein PM, Winston BW. · Immunology Research Group, University of Calgary, Calgary, AB, Canada. · Chest. · Pubmed #12475802 links to  free full text

Abstract: Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor (TGF)-beta, insulin-like growth factor (IGF)-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis (scleroderma). We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in fibrotic lung diseases and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.

Maksymowych WP, Breban M, Braun J. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. · Best Pract Res Clin Rheumatol. · Pubmed #12406430 No free full text.

Abstract: In contrast to rheumatoid arthritis (RA), the concept of disease modification in ankylosing spondylitis (AS) remains to be clarified. Endpoint measures employed in AS trials primarily assess features related to symptomatology while endpoints considered more relevant to the concept of disease modification, such as spinal mobility, acute-phase reactants and radiological progression, either lack sensitivity to change or have not been comprehensively validated. NSAIDs alleviate symptoms of AS but most trials have been short term, precluding meaningful conclusions regarding disease modification. Among disease-modifying therapies used in RA, sulfasalazine has been studied in several controlled trials mostly in patients with longstanding disease, effect sizes being small and limited to those with peripheral synovitis. No conclusions can be drawn from the limited studies evaluating methotrexate.

Ajuebor MN, Swain MG, Perretti M. · Liver Unit, Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada T2N 4N1. · Biochem Pharmacol. · Pubmed #11960595 No free full text.

Abstract: Chemokines and their receptors are a large family of inflammatory molecules responsible for a number of biological functions, including the accumulation of leukocytes at tissue sites. Over the past 10 years, a number of studies have indicated a role for chemokines and chemokine receptors in the pathophysiology of several inflammatory diseases, examples of which are multiple sclerosis, atherosclerosis, rheumatoid arthritis, and gastrointestinal diseases including hepatic disease. For this reason, it is not surprising that modulation of their pharmacology could be a prime target for drug discovery. This commentary provides a brief synopsis of our current knowledge of the role of chemokines and their receptors in the inflammatory process, and highlights the pros and possibly cons of chemokine and chemokine receptor antagonism in the therapeutic approach to several inflammatory diseases.

Russell A, Haraoui B, Keystone E, Klinkhoff A. · Department of Medicine, University of Alberta Hospital Site, Heritage Medical Research Centre, Edmonton, Canada. · Clin Ther. · Pubmed #11768835 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a physically debilitating disease that places an enormous burden not only on individuals and their families but also on the economy. Affecting -1% of the Canadian population, RA is characterized by pain and swelling of joints. Without effective treatment, RA results in joint destruction that often requires surgery. OBJECTIVE: This review summarizes the effect of current and new RA treatments on joint damage, with a focus on infliximab. The health-economic repercussions and potential impact of arresting the joint destruction of RA are discussed. METHODS: Information for inclusion in this review was identified through searches of the MEDLINE and HealthStar databases from 1995 to 2000. Search terms included rheumatoid arthritis, treatment guidelines, economics, and individual drug names. RESULTS: Standard initial RA drug therapy has been aimed at reducing pain and inflammation, whereas use of the more potent disease-modifying antirheumatic drugs (DMARDs) has been reserved for later stages of disease. More aggressive RA treatment involves introducing DMARDs at the earliest stage. The largest single direct cost of RA involves hospital admissions for the correction of joint deformities. Among newer therapies, the anti-tumor necrosis factor-alpha agent infliximab has been shown to arrest radiographic measures of disease progression. CONCLUSIONS: With early and aggressive treatment involving new drugs and drug combinations, it may be possible to ameliorate the physical, social, and economic effects of RA.

Maksymowych WP. · Associate Professor of Medicine, Rheumatic Disease Unit, University of Alberta, 562 Heritage Medical Research Center, Edmonton, AB T6G 2S2, Canada. · Curr Opin Investig Drugs. · Pubmed #11249597 No free full text.

Abstract: Although the spondyloarthropathies constitute amongst the commonest chronic inflammatory joint disorders, there have been few therapeutic advances since the introduction of nonsteroidal anti-inflammatory agents. A number of disease-modifying therapies originally developed for rheumatoid arthritis have also been examined in this class of arthritides, although placebo-controlled studies are lacking. Despite the low interest from industry, there is the promise that emerging therapies, particularly bisphosphonates and tumor necrosis factor alpha antagonists may be efficacious. Significant impediments to the development of additional therapeutic agents include a limited understanding of immunopathological events operative in early disease, disease heterogeneity, the inability to detect structural damage with adequate sensitivity, and the high cost of treatment. However, the recent development of internationally standardized and validated clinical outcome assessment tools as well as sophisticated magnetic resonance imaging are rekindling interest in these disorders.

Peuckmann V, Fisch M, Bruera E. · Department of Pharmacology, University of Alberta, Edmonton, Canada. · Drugs. · Pubmed #10983733 No free full text.

Abstract: Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet's disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren's syndrome, lupus erythematosus and a variety of solid tumours is currently being explored. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities. The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-alpha and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the original uses and teratogenic effects of thalidomide within its historical context and, linking recent research at the molecular level with clinical findings, aims to provide the reader with insight into the current understanding of its biological actions, toxicities and potential benefits.