Rheumatoid Arthritis: Canada

Tugwell P, Idzerda L, Wells GA. · Centre for Global Health, University of Ottawa, 501 Smyth Rd, Rm LM12, Ottawa, ON, K1H8L6, Canada. · Am J Manag Care. · Pubmed #18095786 links to  free full text

Abstract: BACKGROUND: Generic health status measures are commonly used in the evaluation of rheumatoid arthritis (RA) patients. The reliability, validity, and sensitivity of the instruments in the assessment of quality of life (QOL) in RA, and how they correlate to other clinical measurements, have long been questioned. OBJECTIVE: Analyze the performance of a commonly used generic health status measure, the Medical Outcomes Study 36-Item Short Form (SF-36), against the Outcome Measures in Rheumatology (OMERACT) criteria. METHODS: Data were analyzed from 7 double-blind, randomized controlled trials that examined the effectiveness of 1 or more interventions in RA. The primary outcome measures evaluated were the Mental and Physical Component Scores of the SF-36. Comparators were 1 or more of the following: the Health Assessment Questionnaire scores, tender joint count (TJC), the Disease Activity Score, and the American College of Rheumatology Responder Index (ACR20, ACR50, ACR70). The ability to detect a treatment effect in the study outcomes was evaluated using 3 measures: treatment difference, standardized response mean, and relative efficiency in relation to the TJC. RESULTS: As a generic QOL measure, the SF-36 is better suited to capture the holistic health of the patient, as reflected in the World Health Organization definition of health as being not only the avoidance of disease but the physical, emotional, and social well-being of the patient. Furthermore, use of the SF-36 permits comparisons of physical and mental aspects of QOL in the RA patient population, as well as comparisons of QOL parameters between patients with RA, other patient groups, and the general population. CONCLUSION: The SF-36 deserves serious consideration for inclusion in the core set of outcomes in RA trials.

Camfield CS, Camfield PR. · Department of Pediatrics, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada. · Epilepsia. · Pubmed #18047590 No free full text.

Abstract: Children with epilepsy often grow into adults with significant social problems including decreased employment, marriage, social relationships, and independent living arrangements. These problems are noted in population-based longitudinal and cross-sectional studies from many countries. Learning disorder and mental handicap are the most consistent predictors of poor social outcome. Epilepsy variables, even remission, appear to have little effect. The influence of epilepsy on social outcome is greater than found in other childhood chronic disease control groups. More attention and research is needed to correct these unfortunate outcomes.

Reynolds J, Shojania K, Marra CA. · Division of Rheumatology, Faculty of Medicine, University of British Columbia, Vancouver, Canada · Pharmacotherapy. · Pubmed #18041889 No free full text.

Abstract: Rheumatoid arthritis is a chronic autoimmune disease that often leads to functional disability and reduced quality of life. The pathogenesis of synovial inflammation that is associated with this disease is thought to result from T-cell activation. To become fully activated, T cells require an antigen-specific signal through the T-cell receptor and a second signal through a costimulatory receptor. Abatacept is the first drug in a new class of disease-modifying antirheumatic drugs (DMARDs) known as selective costimulation modulators. Costimulation modulators block the second signal and decrease T-cell activation. Abatacept has been approved by the United States Food and Drug Administration for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to at least one other DMARD, such as methotrexate or tumor necrosis factor (TNF)-alpha inhibitors. Randomized controlled trials have shown that abatacept improves both clinical outcomes and health-related quality of life in patients who have had an inadequate response to other DMARDs. Abatacept has been shown to be well tolerated. In clinical trials, however, abatacept treatment was associated with a higher rate of infections compared with placebo. This finding was compounded when abatacept was used with TNF-alpha inhibitors; thus, this combination should be avoided. Abatacept appears to be a useful treatment option for patients with rheumatoid arthritis who have previously failed other DMARDs. However, additional clinical trials evaluating its long-term effect on patient safety and disease outcomes are needed.

Srinivasan S, Slomovic AR. · Department of Ophthalmology, Toronto Western Hospital, and Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada. · Compr Ophthalmol Update. · Pubmed #17999834 No free full text.

Abstract: Sjögren syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltration of the affected glands. The exocrinopathy can be encountered alone (primary Sjögren syndrome or in association with other autoimmune disorders, the three most common ones being rheumatoid arthritis, systemic lupus erythematosus, and progressive systemic sclerosis (secondary Sjögren syndrome). A revised international consensus has been designed based on symptoms and objective signs. Recent studies have broadened our understanding of the etiopathogenesis and immunopathology of primary Sjögren syndrome. Systemic therapy includes treatment of the underlying systemic disorder with steroidal and nonsteroidal agents, disease-modifying agents, and cytotoxic therapy to address the extra glandular manifestations. Medical treatment of dry eye includes aqueous enhancement therapy, anti-inflammatory therapy, and secretagogues. The surgical treatment of dry eye includes punctal occlusion, tarsorrhaphy, and botulinum toxin-induced ptosis. This review highlights recent advances in understanding the underlying mechanisms of the disease as well as the therapeutic options.

Mader R, Keystone E. · Rebecca McDonald Centre for Arthritis and Autoimmune Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · J Rheumatol Suppl. · Pubmed #17985419 No free full text.

Abstract: Disability and joint damage in rheumatoid arthritis (RA) occur rapidly and early in the course of the disease. Disease activity is predominantly responsible for the disability in the early stages of RA. Nonreversible joint damage increases disability later in the course of RA. In recent years, several strategies that employed combination therapies with conventional disease modifying antirheumatic drugs (DMARD) were studied with the aim of rapidly bringing the disease under control. The ultimate goal was to alleviate symptoms and slow or halt the progression of joint damage. The introduction of highly efficient biologic agents allows introduction of a number of new strategies, including early administration of a biologic agent alone or in combination with high-dose methotrexate. Other options for the use of biologic therapies include the use of biologic agents for moderate disease, and early use of a biologic agent for induction of remission and subsequent treatment with a conventional DMARD. A strategy for tight control of disease with targeted outcomes for decision-making may offer further improvement in disease control irrespective of the treatment approach. The remarkably improved outcomes that can be achieved by initiating aggressive therapy early, with close monitoring of disease progression and modification of ineffective therapeutic strategies, support the use of biologics in the optimal management of RA.

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.

Beaulieu P, Ware M. · Department of Anesthesiology and Pharmacology, University of Montréal, Montréal, Québec, Canada. · Curr Opin Anaesthesiol. · Pubmed #17873600 No free full text.

Abstract: PURPOSE OF REVIEW: The aim of this article is to assess the role of cannabinoids in the treatment of acute and chronic pain in humans. RECENT FINDINGS: Very few clinical trials looking at the analgesic effects of cannabinoids in the acute pain settings have been performed. Three recent studies have evaluated the oral administration of synthetic cannabinoids in postoperative pain. At low doses cannabinoids are not different from placebo, whereas at high doses they may be associated with adverse effects or even worsening of pain intensity. In chronic pain patients, the safety and analgesic efficacy of a number of cannabinoid compounds have recently been evaluated in several clinical trials in several chronic pain conditions. While the small size of the trials and the relatively short duration of follow-up limits broad generalization, to date there is increasing evidence that cannabinoids are safe and effective for refractory chronic pain conditions including neuropathic pain associated with multiple sclerosis, rheumatoid arthritis, and peripheral neuropathy associated with HIV/AIDS. SUMMARY: The precise role of cannabinoids in pain treatment still needs further evaluation. Cannabinoid compounds may be more effective in the context of chronic neuropathic pain than for the management of acute pain.

El-Sohemy A. · Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. · Forum Nutr. · Pubmed #17684398 No free full text.

Abstract: Nutrients interact with the human genome to modulate molecular pathways that may become disrupted, resulting in an increased risk of developing various chronic diseases. Genetic polymorphisms affect the metabolism of dietary factors, which in turn affects the expression of genes involved in a number of important metabolic processes. Genetic polymorphisms affecting nutrient metabolism may explain some of the inconsistencies among epidemiological studies relating diet to chronic diseases such as cancer, diabetes, rheumatoid arthritis, osteoporosis and cardiovascular disease. Understanding how genetic variations influence nutrient digestion, absorption, transport, biotransformation, uptake and elimination will provide a more accurate measure of exposure to the bioactive food ingredients ingested. Furthermore, genetic polymorphisms in the targets of nutrient action such as receptors, enzymes or transporters could alter molecular pathways that influence the physiological response to dietary interventions. Among the candidate genes with functional variants that affect nutrient metabolism are those that code for xenobiotic-metabolizing enzymes (also called drug-metabolizing enzymes). These enzymes are involved in the phase I and II biotransformation reactions that produce metabolites with either increased or decreased biological activity compared to the parent compound. A number of dietary factors are known to alter the expression of these genes that, in turn, metabolize a vast array of foreign chemicals including dietary factors such as antioxidants, vitamins, phytochemicals, caffeine, sterols, fatty acids and alcohol. Knowledge of the genetic basis for the variability in response to these dietary factors should result in a more accurate measure of exposure of target tissues of interest to these compounds and their metabolites. Examples of how 'slow' and 'fast' metabolizers respond differently to the same dietary exposures will be discussed. Identifying relevant diet-gene interactions will benefit individuals seeking personalized dietary advice as well as improve public health recommendations by providing sound scientific evidence linking diet and health.

Towheed TE, Hochberg MC, Shea BJ, Wells G. · Queen's University, Medicine and of Community Health and Epidemiology, Etherington Hall-Room 2066, Kingston, Ontario, Canada, K7L 3N6. · Cochrane Database Syst Rev. · Pubmed #17636642 No free full text.

Abstract: BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used as a pharmacologic treatment to relieve pain for patients with OA of the hip. However, these agents are associated with significant toxicity, particularly in the elderly population (age > 65 years). OBJECTIVES: To review all randomized trials of analgesics and anti-inflammatory therapy in osteoarthritis (OA) of the hip. To determine which non-steroidal, anti-inflammatory drug (NSAID) is the most effective, and which NSAID is the most toxic. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register and MEDLINE up to August 1994. Reference lists of all trials were also manually searched. SELECTION CRITERIA: All randomized controlled trials comparing non-steroidal anti-inflammatory drugs (NSAIDs) and/or analgesics in patients with Osteoarthritis. The trials selected for inclusion were identified by one reviewer (TT) and rechecked by a second (MH). DATA COLLECTION AND ANALYSIS: Qualitative assessments were performed using a quality scoring system designed for NSAID trials in rheumatoid arthritis. Both the design and analysis aspects of the trials were evaluated, each aspect being rated on a scale of 0 to 8. A quantitative method, which calculates the ratio of improvement produced by one NSAID to that produced by another, was used to rate the relative efficacy of different NSAIDs with respect to pain relief. Toxicity comparisons were made according to the reviewer findings. All quality assessments were carried out independently by two reviewers (TT, BS). All data abstraction was carried out by one reviewer (TT) and rechecked by two other reviewers (BS, GW). A consensus was reached on discrepancies. MAIN RESULTS: Forty-three trials were identified, and of these, 39 evaluated NSAIDs, while four evaluated only analgesics. The median design and analysis scores were two and four respectively. Six NSAIDs were included in at least five trials. Of these, indomethacin was rated more effective in five of its seven comparisons, but more toxic in seven of 12 comparisons. Only five of the 29 (17%) NSAID comparisons found statistically significant differences in efficacy. Of the 43 RCTs identified only 17 had statistical data available for future pooling for this meta-analysis. In the case where data was missing, authors of the trials will be contacted for inclusion of data in future reviews. AUTHORS' CONCLUSIONS: NSAID trials in patients with OA of the hip appear to be weakened by the lack of standardization of case definition of OA, and also by the lack of standardization of outcome assessments. No clear recommendations for the choice of specific NSAID therapy in hip OA can be offered at this time based on this analysis.

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.

Sauder DJ, King GJ. · Hand and Upper Limb Centre, University of Western Ontario, St Joseph's Health Care, London, Ontario, Canada. · Tech Hand Up Extrem Surg. · Pubmed #17536534 No free full text.

Abstract: Replacement arthroplasty of the ulnar head is indicated primarily for stiffness and pain as a consequence of rheumatoid, degenerative, and posttraumatic arthritis of the distal radioulnar joint. It is also successfully used in the setting of previous failed excisional arthroplasty of the distal ulna. A distal ulnar hemiarthroplasty, which anatomically recreates the native ulnar head by employing an eccentric design, is discussed. The surgical technique includes a dorsal approach and careful repair of the soft tissue stabilizers.

Beauchesne PR, Chung NS, Wasan KM. · Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. · Drug Dev Ind Pharm. · Pubmed #17454054 No free full text.

Abstract: As early as 1978, the immunosuppressive effect of cyclosporine A (CsA), a metabolite of the fungus Tolypocladium inflatum (Borel, 1989), was reported to be effective in inhibiting organ rejection in patients receiving kidney transplants from mismatched cadaver donors (Calne et al., 1978) and in the treatment of graft-versus-host disease in patients with acute leukemia following bone marrow transplants (Powles et al., 1978). Today, CsA is still indicated to prevent rejection following solid organ transplantations, prevent and treat graft-vs-host disease following bone marrow transplants, and has also been used in the treatment of autoimmune disease such as psoriasis, rheumatoid arthritis, and nephrotic syndrome (Canadian Pharmacists Association, 2006). The effectiveness of CsA is derived from its ability to specifically and reversibly inhibit immunocompetent lymphocytes in the G(0) and G(1) phase of the cell cycle. The T-helper cells are the main target, but suppression of the T-suppressor cells also occurs. The production and release of lymphokines, including interleukin-2 are also inhibited (Novartis, 2005a). CsA can be administered intravenously as well as orally in the form of a solution or a soft gelatin capsule. The following review will focus on the evolution of the emulsion-based oral formulations from the first generation as Sandimmune to the second generation Neoral, both products of Novartis Pharmaceutical, as well as on the Sandimmune commercial intravenous formulation. The potential of alternative delivery systems, including micelles, micro- and nanoparticles, and liposomes, will also be discussed.

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.

Davignon J, Leiter LA. · Clinical Research Institute of Montreal, Montreal, QC, Canada. · Vasc Health Risk Manag. · Pubmed #17319096 links to  free full text

Abstract: BACKGROUND: The multiple effects (ie, pleiotropic effects of statins) have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. OBJECTIVE: To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. METHOD: Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000-2004), and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990-2003), abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins' nonlipid (ie, pleiotropic) effect(s). Data were extracted and trial quality was assessed by the authors. RESULTS: Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer's disease, multiple sclerosis, and stroke (outcomes often overlapped). CONCLUSION: Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients.

de Gannes GC, Ghoreishi M, Pope J, Russell A, Bell D, Adams S, Shojania K, Martinka M, Dutz JP. · Department of Dermatology and Skin Science, The Skin Care Centre, 835 West 10th Ave, Vancouver, British Columbia, Canada V5Z 4E8. · Arch Dermatol. · Pubmed #17310002 links to  free full text

Abstract: BACKGROUND: New onset or worsening of psoriasis has been reported in patients treated with tumor necrosis factor alpha (TNF-alpha) inhibitors for a variety of rheumatologic conditions. There is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease, including psoriasis, involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. We present herein a case series with clinical and histopathologic evidence of psoriasis in patients with rheumatologic disease treated with TNF-alpha inhibitors. We propose that the cross regulation between TNF-alpha and IFN may have a role in the pathogenesis of this reaction. OBSERVATIONS: We observed new-onset psoriasis (n = 13) or severe exacerbation of psoriasis (n = 2) in 15 patients with a variety of rheumatologic conditions-rheumatoid arthritis (n = 13), psoriatic arthritis (n = 1), and seronegative arthritis (n = 1)-during treatment with etanercept (n = 6), infliximab (n = 5), and adalimumab (n = 4). Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (MxA, a surrogate marker for lesional type 1 IFN activity) showed increased staining in TNF-alpha inhibitor-induced psoriasis compared with psoriasis vulgaris. CONCLUSIONS: New onset or severe exacerbation of psoriasis is a rare complication of TNF-alpha inhibitor therapy. The finding of increased production of IFN-alpha in TNF-alpha inhibitor-induced psoriasis is a possible pathophysiologic explanation for this reaction.

Chinchalkar SJ, Pitts S. · Department of Hand Therapy, Hand & Upper Limb Centre, St. Joseph's Health Care London, London, Ontario, Canada. · Tech Hand Up Extrem Surg. · Pubmed #17159476 No free full text.

Abstract: The extensor mechanism of the hand is complex, requiring effective functioning of all involved structures, including the sagittal bands. The sagittal bands function to maintain the extensor tendons in midline and to limit their distal excursion. Injury to the sagittal bands or sagittal band attenuation can cause instability and ulnar displacement/subluxation of the extensor tendons into the valleys between the digits and lead to a subsequent loss of active finger extension at the metacarpophalangeal joints. Secondary conditions may also develop, such as swan-neck deformity, as is frequently observed in the rheumatoid arthritis population. To prevent or reduce an extension lag and secondary changes and to maintain the functional use of the hand, a dynamic metacarpophalangeal extension assist splint is necessary. This splint enables extension at the metacarpophalangeal joints, thus enabling the functional use of the hand. This article reviews the biomechanics of the sagittal bands and the corrections that enable finger extension at the metacarpophalangeal joints, thus preventing secondary conditions.

Bernatsky S, Lee JL, Rahme E. · Division of Clinical Epidemiology, McGill University Health Centre, 687 Pine Avenue West, V Building, Montreal, Quebec H3A 1A1, Canada. · Rheumatology (Oxford). · Pubmed #17148471 links to  free full text

Abstract: OBJECTIVE: Recent research has focused on the effects of corticosteroids and non-steroidal anti-inflammatory drugs/agents (NSAIDs) on non-Hodgkin's lymphoma (NHL) risk, with inconclusive results. We conducted meta-analyses of data published to date, to ascertain the over-all association between NHL and corticosteroid use, and between NHL and NSAID use. METHODS: Literature searches were performed to find studies assessing the effects of corticosteroids and/or NSAIDs on NHL risk. We analysed nine case-control studies and one cohort study of the effect of corticosteroids and/or NSAIDs on NHL risk. We performed a formal meta-analysis using summary measures from these studies. RESULTS: The studies contributed 6897 NHL cases and 8881 controls for the corticosteroid analyses, and 5794 NHL cases and 34,707 controls for the NSAID analyses. There was no heterogeneity of the odds ratio (OR) estimates. The overall OR for the effect of corticosteroid exposure on NHL occurrence was not suggestive of an increased risk [OR 1.09, 95% confidence interval (CI) 0.96-1.24]. Similarly, the OR for the effect of NSAIDs on NHL occurrence did not support an increased risk (OR 0.93, 95% CI 0.74-1.14). CONCLUSIONS: Our meta-analyses suggest little evidence that corticosteroid or NSAID exposures are themselves risk factors for NHL. Early data linking corticosteroids and/or NSAIDs with NHL may reflect an underlying increased risk of lymphoma in patient populations that use these medications (i.e. autoimmune diseases such as rheumatoid arthritis), and may point to the importance of disease activity in driving NHL risk in these populations.

Wells G, Boers M, Tugwell P, Anonymous00204. · Department of Epidemiology and Community Medicine, University of Ottawa,Ottawa, Ontario, Canada. · Clin Exp Rheumatol. · Pubmed #17083764 No free full text.

Abstract: With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. MDA is between high disease activity and remission and anyone in remission will also be in MDA. This paper summarizes the process of coming to a definition of minimal disease activity in rheumatoid arthritis. Two equivalent preliminary definitions of minimal disease activity for use as secondary outcome measures in clinical trials in RA are proposed: a core-set definition based on the WHO/ILAR core set and a DAS-based definition based on the DAS28.

Brockhausen I. · Department of Biochemistry, Human Mobility Research Centre, Queen's University, Kingston, Ontario, Canada. · Drug News Perspect. · Pubmed #17080203 No free full text.

Abstract: The immune system relies on cellular communication and often on the recognition of carbohydrates by mammalian lectins. Galactose (Gal)-containing structures are involved in both the innate and adaptive immune systems. Gal is a ligand for Gal/N-acetylgalactosmine (GalNAc) receptors and galectins, and is part of the scaffold structure that synthesizes oligosaccharide ligands for selectins, siglecs and other lectins of the immune system. Gal residues are added to glycoproteins and glycolipids by members of a large family of galactosyltransferases. The expression of many of these enzymes is regulated by the action of cytokines, and becomes altered in various disease states. Specific galactosyltransferases have been shown to control cell adhesion and leukocyte functions. Antibodies need to be galactosylated for normal function, and undergalactosylated immunoglobulin (Ig) is associated with rheumatoid arthritis, while Gal is lacking in the IgA of patients with IgA nephropathy. Interactions involving Gal play important roles in host defenses; they can also result in serious pathophysiology. Galactosyltransferases represent potential targets for the control of cell growth and apoptosis, inflammation and infections.

Keystone EC. · University of Toronto, Canada. · Nat Clin Pract Rheumatol. · Pubmed #17075598 No free full text.

Abstract: Recent data have shown that disability and joint destruction in rheumatoid arthritis (RA) occur early on in the course of the disease and progress rapidly. It has been shown that in the early stages of RA, disability is attributed to increased disease activity, whereas later in the course of the disease, disability results from irreversible joint damage. These findings support the need to develop treatment strategies that will rapidly bring the disease under control, with the ultimate goal of alleviating symptoms and halting progressive joint damage. A number of such strategies have been evaluated, including the early administration of a biologic agent alone or in combination with high-dose methotrexate. Other, more recent treatment strategies include the tight control of disease activity by targeting specific outcomes necessary for decision making; the use of biologic agents for the treatment of moderate disease; and the induction of remission with a biologic agent early in the course of disease, followed by maintenance therapy using a conventional disease-modifying antirheumatic drug. The substantial positive effect these strategies have on patient outcomes supports the concept that the optimal management of RA involves aggressive early therapy combined with close monitoring of disease progression and modification of ineffective therapeutic strategies.

Keystone EC. · University of Toronto, Canada. · Nat Clin Pract Rheumatol. · Pubmed #17075592 No free full text.

This publication has no abstract.

Gladman DD. · Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, 399 Bathurst Street, 1E 410B, Toronto, Ontario, M5T 2S8, Canada. · Ann Rheum Dis. · Pubmed #17038466 No free full text.

This publication has no abstract.

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.

McCulloch CA, Downey GP, El-Gabalawy H. · CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Canada M5S 3E2. · Nat Rev Drug Discov. · Pubmed #17016427 No free full text.

Abstract: Therapeutically controlling inflammation is essential for the clinical management of many high-prevalence human diseases. Drugs that block the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukin-1 (IL-1) can improve outcomes for rheumatoid arthritis and other inflammatory diseases but many patients remain refractory to treatment. Here we explore the need for developing new types of anti-inflammatory drugs and the emergence of novel drug targets based on the clustering of IL-1 receptors into multi-protein aggregates associated with cell adhesions. Interference with receptor aggregation into multi-protein complexes effectively abrogates IL-1 signalling. The exploration of the crucial molecules required for receptor clustering, and therefore signal transduction, offers new targets and scope for anti-inflammatory drug development.

Harauz G, Musse AA. · Department of Molecular and Cellular Biology, and Biophysics Interdepartmental Group, University of Guelph, 50 Stone Road East, Guelph, ON, Canada, N1G 2W1. · Neurochem Res. · Pubmed #16900293 No free full text.

Abstract: Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.