Rheumatoid Arthritis: Canada

Laxer RM. · Department of Pediatrics and Medicine, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. · Pediatr Clin North Am. · Pubmed #15820370 No free full text.

This publication has no abstract.

Miller E, Roposch A, Uleryk E, Doria AS. · Department of Diagnostic Imaging, Hamilton Health Science, McMaster University, 1200 Main Street West, Room 2SRAD, Hamilton, ON L8N 3Z5, Canada. · Acad Radiol. · Pubmed #19427982 No free full text.

Abstract: RATIONALE AND OBJECTIVES: The aim of this study was to systematically review the quality of papers on the clinimetric properties of magnetic resonance imaging for the diagnosis of juvenile idiopathic arthritis in peripheral joints. MATERIALS AND METHODS: A review of Medline, EMBASE, the Database of Abstracts of Reviews of Effects, and the Cochrane Library was performed by using a systematic search strategy. Two independent reviewers evaluated selected articles by using Standards for Reporting of Diagnostic Accuracy (STARD) and Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tools. Items were reported independently for STARD and QUADAS. RESULTS: Eighteen studies (validity, n = 18; reliability, n = 3; responsiveness, n = 3) were included. Their overall quality of reporting of methods was fair. Methodological problems with the STARD system included a lack of reporting of exclusion criteria (n = 14), partial or no information on operators' expertise (n = 14) or blinding (n = 18), and deficient information on study time frames (n = 12), treatments (n = 10), or indeterminate results (n = 18). The distribution of QUADAS scores was heterogeneous, with overall scores ranging between 3.5 (poor) and 16.5 (excellent) (maximum score, 17.5). CONCLUSIONS: The quality of reporting of methods in studies on the magnetic resonance imaging assessment of juvenile idiopathic arthritis is heterogeneous and fair overall. Further methodological refinement of research design should be sought in future studies to provide stronger evidence for the value of novel techniques in clinical settings.

Miller E, Uleryk E, Doria AS. · Department of Radiology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada. · AJR Am J Roentgenol. · Pubmed #19380543 No free full text.

Abstract: OBJECTIVE: Our objective was to semiquantitatively evaluate the diagnostic accuracy of MRI for evaluation of synovium and cartilage of peripheral joints in juvenile idiopathic arthritis (JIA) according to the levels of evidence and recommendations of the Canadian Task Force on Periodic Health Examination guidelines. CONCLUSION: Articles were screened using MEDLINE, EMBASE, DARE, and the Cochrane Library. Two independent reviewers assessed whether the currently available MRI techniques are accurate for diagnosis of synovial hypertrophy and cartilage degeneration in children with JIA. Overall, there is fair (grade B) strength of evidence that MRI is an accurate diagnostic method for evaluating synovium and cartilage and for assessing clinical responsiveness to treatment in peripheral joints in JIA.

Keystone E. · The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, University of Toronto, Toronto, Ontario, Canada. · Curr Opin Rheumatol. · Pubmed #19365267 No free full text.

Abstract: PURPOSE OF REVIEW: To provide an update on new concepts in the inhibition of radiographic progression with current and emerging biologic therapy. RECENT FINDINGS: The advent of biologic therapies for the treatment of rheumatoid arthritis has given rise to the concept of a disconnect between clinical and radiographic outcomes. Radiographic progression has been observed in patients in clinical remission, whereas inhibition of radiographic progression has been demonstrated in patients with clinically active disease. Moreover, imaging remission has been shown to be much easier to achieve than clinical remission. Biologics are superior to methotrexate (MTX) in inhibiting radiographic progression at every level of disease activity and response. The majority of patients receiving biologics and a significant proportion receiving MTX alone do not progress radiographically. The combination of a biologic and MTX inhibits radiographic progression more than either alone, reducing both the proportion of patients progressing and the degree of progression of those who do progress. Although biologics are similar in their ability to inhibit radiographic progression in most patients, they differ in inhibiting the progression in the rapid radiographic progressors. SUMMARY: The disconnect between clinical and radiographic outcomes demonstrated with biologics implies the need to monitor both outcomes in order to treat patients most effectively. The superiority of biologics over MTX in inhibiting radiographic progression suggests that the clinical target for a biologic may differ from that for MTX to prevent structural damage and preserve function. For most patients, radiographic inhibition should not affect the choice of a biologic.

Veillette A, Rhee I, Souza CM, Davidson D. · Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada. · Immunol Rev. · Pubmed #19290936 No free full text.

Abstract: The proline-, glutamic acid-, serine- and threonine-rich (PEST) family of protein tyrosine phosphatases (PTPs) includes proline-enriched phosphatase (PEP)/lymphoid tyrosine phosphatase (LYP), PTP-PEST, and PTP-hematopoietic stem cell fraction (HSCF). PEP/LYP is a potent inhibitor of T-cell activation, principally by suppressing the activity of Src family protein tyrosine kinases (PTKs). This function seems to be dependent, at least in part, on the ability of PEP to bind C-terminal Src kinase (Csk), a PTK also involved in inactivating Src kinases. Interestingly, a polymorphism of LYP in humans (R620W) is a significant risk factor for autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and lupus. The R620W mutation may be a 'gain-of-function' mutation. In non-hematopoietic cells, PTP-PEST is a critical regulator of adhesion and migration. This effect correlates with the aptitude of PTP-PEST to dephosphorylate cytoskeletal proteins such as Cas, focal adhesion associated-kinase (FAK), Pyk2, and PSTPIP. While not established, a similar function may also exist in immune cells. Additionally, overexpression studies provided an indication that PTP-PEST may be a negative regulator of lymphocyte activation. Interestingly, mutations in a PTP-PEST- and PTP-HSCF-interacting protein, PSTPIP1, were identified in humans with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and familial recurrent arthritis, two autoinflammatory diseases. These mutations abrogate the ability of PSTPIP1 to bind PTP-PEST and PTP-HSCF, suggesting that these two PTPs may be negative regulators of inflammation.

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.

Bansback N, Marra CA, Finckh A, Anis A. · Centre for Health Evaluation and Outcome Sciences, St Paul's Hospital, BC, Canada. · Best Pract Res Clin Rheumatol. · Pubmed #19233048 No free full text.

Abstract: Recent years have witnessed a shift in the therapeutic approach for patients with early rheumatoid arthritis (RA). The focus of interest has been the improved outcomes achieved through the use of early aggressive disease-modifying therapy, including the use of biologic agents. Such strategies have acquisition costs which typically exceed those of older anti-rheumatic strategies. However, improved outcomes might lead to fewer hospitalizations and physician visits and improved employability, leading to future cost savings. This is in addition to the health benefits which patients value as improvements in quality of life. With many services competing to spend often limited health-care budgets, information on the relative benefits and costs of new approaches for treating RA can be useful in deciding on efficient allocation and treatment decisions.

El-Gabalawy H. · University of Manitoba, Manitoba, Canada. · Best Pract Res Clin Rheumatol. · Pubmed #19233045 No free full text.

Abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disorder based in the synovium of peripheral joints. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are autoantibodies detectable in the majority of patients, with the latter being highly specific for RA. Retrospective studies utilizing preclinical serum samples have demonstrated that RF and ACPAs are detectable in the serum of RA patients months to years before disease onset. Moreover, a close association between ACPAs, smoking, and disease-predisposing HLA-DRB1 alleles has been identified, suggesting that these risk factors may converge to precipitate autoantibody-positive RA. Animal models of RA have added considerable information regarding the immune events that precede joint inflammation. These models have demonstrated that autoantibodies to ubiquitous antigens can directly precipitate chronic organ-specific inflammation centred in the joint. Furthermore, it has recently been possible to demonstrate a role for ACPAs in the animal models of RA. The major challenge currently is to develop a robust predictive model for RA onset, identifying the factors that serve to initiate, amplify, and mature the immune responses towards citrullinated autoantigens. Recent data from a high-risk population of RA family members indicate that the nature and specificity of the ACPA response in healthy individuals differs considerably from that in RA patients, and support the concept that this autoimmune response evolves over time and leads to the onset of clinically detectable synovitis. Ultimately, the availability of data from prospective studies of RA onset will allow for novel strategies that can potentially prevent disease in high-risk individuals.

Rao P, Knaus EE. · Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. · J Pharm Pharm Sci. · Pubmed #19203472 links to  free full text

Abstract: PURPOSE: NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. METHODS: Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. RESULTS: A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. CONCLUSIONS: A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.

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.

Katchamart W, Trudeau J, Phumethum V, Bombardier C. · Rheumatology Division, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Ann Rheum Dis. · Pubmed #19054823 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis. METHOD: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy. RESULTS: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations. CONCLUSION: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

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.

Leombruno JP, Einarson TR, Keystone EC. · University of Toronto, Department of Pharmaceutical Sciences, Toronto, Ontario, Canada. · Ann Rheum Dis. · Pubmed #18753157 No free full text.

Abstract: OBJECTIVE: To evaluate the safety of biological treatments for rheumatoid arthritis (RA) using results from randomised controlled trials (RCT). METHODS: The literature was searched to December 2007 for RCT evaluating inhibitors of tumour necrosis factor alpha (anti-TNF) for RA. Safety data were abstracted and risk estimates were calculated using three approaches, meta-analysis with and without adjustment for exposure and simple exposure-adjusted pooling. RESULTS: Eighteen randomised trials involving 8808 RA subjects were included. Treatment with recommended doses of anti-TNF found no increase in the odds of death (odds ratio (OR) 1.39; 95% CI 0.74 to 2.62), serious adverse events (OR 1.11; 95% CI 0.94 to 1.32), serious infection (OR 1.21; 95% CI 0.89 to 1.63), lymphoma (OR 1.26; 95% CI 0.52 to 3.06), non-melanoma skin cancers (OR 1.27; 95% CI 0.67 to 2.42) or the composite endpoint of non-cutaneous cancers plus melanomas (OR 1.31; 95% CI 0.69 to 2.48) when evaluated using the unadjusted meta-analytic method. Risk estimates were similar with the other methods. For subjects who received two to three times the recommended doses of anti-TNF the risk of serious infection was increased with the unadjusted meta-analytic and pooled analysis, (OR 2.07; 95% CI 1.31 to 3.26) and (risk ratio (RR) 1.83; 95% CI 1.18 to 2.85), respectively, but not increased in the exposure-adjusted meta-analysis (RR 1.99; 95% CI 0.90 to 4.37). Meta-regression identified that the risk of serious infection with anti-TNF therapy decreases with increasing trial duration (p = 0.035). CONCLUSION: Meta-analytic and exposure-adjusted pooled analyses on over 8800 RA subjects in RCT treated over an average of 0.8 years did not identify an increased risk of serious adverse events with recommended doses. High-dose anti-TNF therapy was associated with a twofold increase in the risk of serious infections.

Li LC, Badley EM, MacKay C, Mosher D, Jamal SW, Jones A, Bombardier C. · University of British Columbia and Arthritis Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC, Canada. · Arthritis Rheum. · Pubmed #18668611 No free full text.

This publication has no abstract.

Xie F. · St. Joseph's Health Care Hamilton and McMaster University, Hamilton, Ontario, Canada. · Arthritis Rheum. · Pubmed #18576305 links to  free full text

This publication has no abstract.

McNicol A, Israels SJ. · Department of Oral Biology, University of Manitoba, Winnipeg, Manitoba, Canada. · Cardiovasc Hematol Disord Drug Targets. · Pubmed #18537597 No free full text.

Abstract: Platelets play a complex role in hemostasis and thrombosis. The expression of multiple membrane receptors, both constitutive and activation-dependent, mediates platelet adhesion and aggregation at sites of vascular lesion. Platelet activation leads to exocytosis of granular constituents, release of newly synthesized mediators, and discharge of membrane-bound transcellular signaling molecules. Many of the same mechanisms that play a role in hemostasis and thrombosis facilitate platelet participation in other physiological or pathological processes including inflammation, malignancy and the immune response. Platelet receptors such as GPIb/IX/V, P-selectin, P-selectin glycoprotein ligand 1, CD40 and the alphaIIbbeta3 integrin, crucial to hemostasis, have been implicated in the progression of such inflammatory conditions as atherosclerosis, rheumatoid arthritis and inflammatory bowel disease, in the progression and metastatic spread of malignancies, and in the immune response to bacterial challenge. The release of platelet granular contents, including adhesive proteins, growth factors and chemokines/cytokines, that serve to facilitate hemostasis and wound repair, also function in acute and chronic inflammatory disease and in tumor cell activation and growth. Platelets contribute to host defence as they recognise bacteria, recruit traditional immune cells to the site of infection and secrete bactericidal mediators. The primary focus of this review is the "non-haemostatic" functions of platelets in physiological and pathological states.

Kean WF, Kean IR. · Department of Medicine (Rheumatology), McMaster University, Hamilton, L8N 1T8, Ontario, Canada. · Inflammopharmacology. · Pubmed #18523733 No free full text.

Abstract: Since the dawn of civilization, elemental gold and gold compounds have been revered and utilized by Shamen and medical practitioners alike for many varied pathological problems. In the 20(th) century following the observations of Jacques Forestier, injectable gold compounds were successfully used for the treatment of rheumatoid arthritis. Of the many compounds developed, gold sodium thiomalate has been the most extensively studied by basic scientists and by clinicians. In the1980s, the oral gold compound auranofin showed promise as a therapeutic contender to injectable gold, but the clinical side effect profile and fear of long term effects of immune suppression by auranofin, resulted in gold sodium thiomalate continuing as the preferred gold compound for rheumatoid treatment. However, the increased use and demonstration of effectiveness of low dose Methotrexate (MTX) in rheumatoid treatment over the last 20 years has resulted in a significant decline in the use of injectable gold sodium thiomalate, this despite the claims and evidence that it remains a useful agent in the management of rheumatoid arthritis. Several authors still contend that the injectable gold compounds can still play a valuable role, and indeed may be the correct first choice in the management of rheumatoid arthritis.

Azouz EM. · Radiology Department, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada. · Pediatr Radiol. · Pubmed #18470449 No free full text.

This publication has no abstract.

Bansback N, Ara R, Karnon J, Anis A. · Centre for Health Evaluation and Outcome Sciences, St Paul's Hospital, Vancouver, British Columbia, Canada. · Pharmacoeconomics. · Pubmed #18429656 No free full text.

Abstract: We reviewed the clinical measures used in rheumatoid arthritis (RA) economic evaluations with respect to their relevance and sensitivity to changes in survival, health-related quality of life (HR-QOL) and costs. We compared the measures from the economic perspective and discussed the validity of methods used to extrapolate beyond the trial data. Cost-effectiveness evaluations of disease-modifying antirheumatic drugs in RA were identified by searching MEDLINE, EMBASE, Econlit and NHS EED databases. Studies were retained if they extrapolated beyond randomized controlled trial evidence using relationships between clinical measures, costs and utilities.In the 22 studies identified, clinical severity was measured using the Health Assessment Questionnaire (HAQ) Disability Index, the American College of Rheumatology (ACR) response criteria, the Disease Activity Score (DAS) or a combination of the HAQ and DAS. The HAQ is correlated with mortality, costs and HR-QOL instruments, and several studies used linear relationships to model these associations. However, a polynomial relationship or discrete states may be more appropriate for patients at the extremes of the disease spectrum, and numerous HAQ health states may be required to capture differences in mortality risk. While the ACR response criteria is a more comprehensive measure than the HAQ, it is a relative measure, which creates difficulties when estimating absolute changes in HR-QOL, costs and mortality risk. The evidence base linking DAS scores with HR-QOL instruments, costs and mortality is less robust, possibly due to the comparatively recent development of the measure and the limited number of possible scores (mild/moderate/severe). While there is some evidence of a relationship between DAS scores and costs, the DAS does not capture all aspects of HR-QOL, and no significant relationship has been established with mortality risk.Evidence suggests the HAQ to be the primary clinical measure for use in economic evaluations as it is measured in almost all clinical studies, and is closely correlated to health utilities, mortality and costs. While new developments suggest the sensitivity of health states may be improved by combining the HAQ with measures such as the DAS, further research is required in this area. Further research is also required to explore the advantages in using either continuous or discrete health states.

Tugwell P, Idzerda L, Wells GA. · Centre for Global Health, Universityof Ottawa, 501 Smyth Rd, Rm LM12, Ottawa, ON, K1H8L6, Canada. · Am J Manag Care. · Pubmed #18415966 No 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 longbeen 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.

Steiner G, Urowitz MB. · Department of Medicine, Division of Endocrinology, Toronto General Hospital and University of Toronto, Ontario, Canada. · Semin Arthritis Rheum. · Pubmed #18395771 No free full text.

Abstract: OBJECTIVE: To describe the impact of rheumatoid arthritis (RA), and its treatment, on lipoprotein levels with potential implications for atherosclerosis. METHODS: A PubMed literature search was undertaken for studies published between 1990 and May 2007, using the search terms "rheumatoid arthritis" AND "lipid" OR "lipoprotein," and including all relevant drug treatment terms for glucocorticoids, disease-modifying antirheumatic drugs, and biologics. RESULTS: Patients with RA face an increased risk of developing premature cardiovascular disease and limited ability to modify risk factors, eg, through exercise. RA is associated with an abnormal lipoprotein pattern, principally low levels of high density lipoprotein (HDL) cholesterol. Most treatments for RA tend to improve the atherogenic index (total/HDL cholesterol ratio), with more evidence for biologics in this regard. The improvement in the lipoprotein profile in RA appears to be associated with suppression of inflammation. CONCLUSIONS: Lipid levels should be monitored and managed in patients with RA to minimize the long-term risk of cardiovascular disease. More research is needed to quantify the relationship between systemic inflammation and lipoprotein levels and to determine the impact of specific lipoprotein particles, eg, small dense low-density lipoprotein and subfractions of HDL on long-term risk. Control of inflammation may have an effect on modifying cardiovascular risk.

Luk T, Malam Z, Marshall JC. · Department of Surgery and the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada. · J Leukoc Biol. · Pubmed #18252866 links to  free full text

Abstract: Pre-B cell colony-enhancing factor (PBEF), also known as visfatin, is a highly conserved, 52-kDa protein found in living species from bacteria to humans. Originally a curiosity identified serendipitously in microarray studies but having no obvious functional importance, PBEF has now been shown to exert three distinct activities of central importance to cellular energetics and innate immunity. Within the cell, PBEF functions as a nicotinamide phosphoribosyl transferase, the rate-limiting step in a salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. By virtue of this role, it can regulate cellular levels of NAD and so impact not only cellular energetics but also NAD-dependent enzymes such as sirtuins. Although it lacks a signal peptide, PBEF is released by a variety of cells, and elevated levels can be found in the systemic circulation of patients with a variety of inflammatory diseases. As an extracellular cytokine, PBEF can induce the cellular expression of inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. Finally, PBEF has been shown to be an adipokine expressed by fat cells that exerts a number of insulin mimetic and antagonistic effects. PBEF expression is up-regulated in a variety of acute and chronic inflammatory diseases including sepsis, acute lung injury, rheumatoid arthritis, inflammatory bowel disease, and myocardial infarction and plays a key role in the persistence of inflammation through its capacity to inhibit neutrophil apoptosis. This review summarizes the admittedly incomplete body of emerging knowledge about a remarkable new mediator of innate immunity.

Ichim TE, Zheng X, Suzuki M, Kubo N, Zhang X, Min LR, Beduhn ME, Riordan NH, Inman RD, Min WP. · University of Western Ontario, Departments of Surgery, Pathology, Microbiology & Immunology, 339 Windermere Road, University Hospital C9-136, London, Ontario, N6A 5A5, Canada. · Expert Opin Biol Ther. · Pubmed #18194075 No free full text.

Abstract: BACKGROUND: Immunotherapy offers the promise of antigen-specific suppression of pathological immune responses in conditions such as autoimmunity and organ transplantation. Substantial advances have been made in recent years in terms of understanding basic immunological mechanisms of autoreactivity, as well as clinically implementing immune-based therapies that are antigen nonspecific. OBJECTIVE: To provide an integrated overview of the current state of the art in terms of antigen-specific tolerance induction, as well as to predict future directions for the field. METHODS: Examples of successes and failures of antigen-specific immunotherapy were sought. Particular attention was paid to the well-established collagen II-induced model of arthritis. RESULTS/CONCLUSIONS: Previous failures of antigen-specific immunotherapy were associated with lack of identification of clinically relevant antigens, as well as inappropriate tolerogenic methodologies. The advances in proteomics combined with novel gene-specific immune modulatory techniques place today's translational researchers in a unique position to tackle the problem of antigen-specific immunotherapeutic protocols.

Setty AR, Choi HK. · Division of Rheumatology, Department of Medicine, University of British Columbia, Arthritis Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z 1L7, Canada. · Curr Rheumatol Rep. · Pubmed #18177597 No free full text.

Abstract: Recent studies have added to our knowledge of the epidemiology of psoriatic arthritis (PsA) across various populations. Absence of a standard case definition and the relative rarity of PsA may have contributed to the paucity of available data to date. Reported prevalence estimates appear to vary more than incidence estimates. Prevalence estimates may vary as a result of differences in genetic factors, exposure to environmental factors, and study methods. Although prevalence data among different subgroups and extrapolation from clinical and laboratory data allow some inferences about the role of various potential risk factors for PsA, only one study has investigated them specifically. Overall, quality of life in PsA appears similar to that in rheumatoid arthritis, whereas available data on the mortality impact of PsA are conflicting, preventing a unified conclusion. This review summarizes recent data on PsA epidemiology.