Rheumatoid Arthritis: Edmonton

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Suarez-Almazor ME, Kaul P. · Department of Public Health Sciences, Faculty of Medicine & Oral Health Sciences, University of Alberta, Edmonton, Canada. · Curr Opin Rheumatol. · Pubmed #10319213 No free full text.

Abstract: In the past year, several publications have reported on aspects of health services research in regard to musculoskeletal disorders. Utilization studies in the elderly have shown that an effective procedure such as hip arthroplasty may be underused in this population. As well, surgical complications in these patients appear to vary according to the number of procedures performed in a hospital, with high-volume hospitals showing better outcomes. Studies of practice patterns show variations among rheumatologists in the treatment of various rheumatic diseases. Practice variations between physician groups, in particular, rheumatologists versus primary care providers, have also been reported. Several studies show that primary care physicians may have some difficulties in diagnosing common rheumatic disorders. There is some evidence as well that rheumatologists may provide better care for some conditions, such as rheumatoid arthritis. These findings have major implications for restrictions to patient access to specialist care by health organizations. A variety of clinical practice guidelines have been developed and tested, most aimed at general practitioners. Physician compliance with guidelines continues to be low for most implementation strategies. Multidisciplinary programs for the treatment of rheumatoid arthritis appear to have a somewhat beneficial effect. Programs based only on patient education appear to have short-term gains, and longer-term effects are diluted because of noncompliant behaviors.

Daneshtalab N, Lewanczuk RZ, Russell AS, Jamali F. · Faculty of Pharmacy, University of Alberta, Edmonton, Alberta, Canada, T6G-2N8. · J Clin Pharmacol. · Pubmed #17050800 No free full text.

Abstract: Inflammatory conditions, such as rheumatoid arthritis, reduce response to calcium channel and beta-adrenergic antagonists but not the angiotensin II type 1 receptor (AT(1)R) antagonist valsartan. Inflammation also reduces clearance of some drugs or active metabolite, thereby reducing response. Active (n = 14) and controlled rheumatoid arthritis (n = 12) and healthy subjects (n = 12) received losartan (100 mg). Blood pressures were measured, and samples were taken for pharmacokinetic and inflammatory mediator concentration determination. Active disease significantly increased arthritic index, nitric oxide, and Creactive protein. Although no between-group difference in plasma losartan concentration-time curves was observed, concentrations of the active metabolite, EXP 3174, were significantly reduced by arthritis. This, however, was not accompanied by reduced clinical response. One subject produced no detectable concentrations of EXP 3174 likely due to insufficient CYP2C9 activity. Despite reduced concentrations of the active metabolite, AT1R antagonists potency does not appear to be reduced by inflammation.

Maksymowych WP, Poole AR, Hiebert L, Webb A, Ionescu M, Lobanok T, King L, Davis JC. · Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. · J Rheumatol. · Pubmed #16206346 No free full text.

Abstract: OBJECTIVE: Anti-tumor necrosis factor-alpha (TNF-alpha) therapies are not only beneficial for reducing symptoms in rheumatoid arthritis (RA) but also for structural damage visible on plain radiographs and serological biomarkers of articular cartilage damage. It is not known if these therapies also prevent structural damage in ankylosing spondylitis (AS). The low sensitivity to change over time of plain radiographic instruments mandates a search for the effects of these therapies on possible biomarkers of cartilage damage. METHODS: We studied 2 populations of patients with AS: (1) patients recruited to a placebo controlled trial of etanercept in AS for 16 weeks; (2) an observational cohort receiving infliximab for disease refractory to conventional therapy. Clinical (morning stiffness, nocturnal pain, Bath AS Disease Activity Index) and laboratory [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] assessments of disease activity were performed at baseline and at either 16 weeks (clinical trial cohort) or at 14 weeks (observational cohort). We measured serum matrix metalloproteinase-1 (MMP-1), MMP-3, human cartilage glycoprotein-39 (YKL-40), and cartilage oligomeric matrix protein by ELISA at the same timepoints. We also measured serum concentrations of 2 novel biomarker epitopes, C2C and 846, by competitive ELISA. The C2C assay detects a neoepitope at the carboxy terminus of the long three-quarter amino-terminal fragment generated following cleavage of type II collagen by collagenases. Aggrecan 846 epitope is a chondroitin sulfate epitope present on intact aggrecan molecules. Both these assays would detect products originating from both hyaline cartilages and intervertebral discs. RESULTS: There was a significant reduction in levels of C2C (p = 0.005) and a significant increase in the 846 epitope (p = 0.01) in patients who received etanercept compared to placebo controls. Changes in C2C correlated significantly with changes in ESR (r = 0.51, p = 0.04) and CRP (r = 0.48, p = 0.048). Significant changes in C2C were not evident in the infliximab observational cohort, although significant reductions were noted in levels of MMP-3 (p = 0.04) and MMP-1 (p = 0.02) at 14 weeks that were not observed in the etanercept group. Analysis of all baseline samples showed a significant correlation between levels of MMP-3 with CRP (r = 0.73, p < 0.0001), and YKL-40 (r = 0.71, p < 0.0001). No correlation was evident at baseline between levels of C2C or 846 epitope and either acute phase reactants or other biomarkers. CONCLUSION: Our data suggest that an anti-TNF-alpha agent, etanercept, may modify cartilage turnover. These include decreased degradation of type II collagen and increased turnover of aggrecan. Additional therapeutic properties of some anti-TNF-alpha agents in AS, such as infliximab, may be related to decreased expression of MMP. Additional studies in larger populations are therefore warranted.

Daneshtalab N, Lewanczuk RZ, Russell A, Jamali F. · Faculty of Pharmacy and Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2N8. · J Clin Pharmacol. · Pubmed #14973301 No free full text.

Abstract: Inflammatory conditions decrease the cardiovascular response to calcium channel and beta-adrenergics blockers due, likely, to down-regulation of the receptors mediated by pro-inflammatory mediators such as C-reactive protein (CRP), nitric oxide (NO), and tumor necrosis factor. The purpose of this investigation was to determine whether down-regulation is also evident in angiotensin II type 1 receptors (AT(1)R) during varying inflammatory states. Normotensive subjects were divided into three groups according to the severity of disease: 14 with active rheumatoid arthritis, 12 with controlled rheumatoid arthritis, and 12 healthy control subjects. The AT(1)R antagonist valsartan (160 mg) was given to all the subjects, and blood samples were taken for pharmacokinetic analysis. The systolic, diastolic, and mean arterial pressures were determined at all blood collection times. The degree of inflammation was measured using joint swelling, NO, and CRP. Plasma valsartan concentration was measured using high-performance liquid chromatography (HPLC). Patients with active disease had significantly higher joint swelling, NO, and CRP than other groups. Plasma valsartan concentration-time curves were remarkably similar in all groups. No reduced response was noticed. Our preliminary observation suggests a need for further studies to examine the possibility of AT(1)R antagonists as alternatives to other cardiovascular drugs so that their potency may be reduced by inflammation.

Allen M, Oberle K, Grace M, Russell A. · Faculty of Nursing, University of Alberta, Edmonton, Canada. · Biol Res Nurs. · Pubmed #12003439 No free full text.

Abstract: The purpose of this phase II clinical trial was to examine safety of elk velvet antler taken concurrently with rheumatoid arthritis medications and to determine efficacy by dose to enable sample size estimation and dose standardization for a larger study. Forty patients with stage II rheumatoid arthritis were randomly assigned to 1 of 4 arms of 10 patients each. One group received placebo and the other 3 groups received 2, 4, or 6 capsules (215 mg) of elk velvet antler with appropriate placebos to total 6 capsules daily. All subjects continued to take their arthritis medications. Outcome variables were reported adverse events and health status. At 1 month, there were no significant differences between groups in number of adverse events or health status. The greatest improvement was in the 6 elk velvet antler group, the least was in the placebo group. Differences were not statistically significant. It was concluded that elk velvet antler can be taken safely in conjunction with a number of rheumatoid arthritis medications and should be studied further to assess efficacy.

Maksymowych WP, Blackburn WD, Tami JA, Shanahan WR. · Department of Medicine, University of Alberta, Edmonton, Canada. · J Rheumatol. · Pubmed #11908555 No free full text.

Abstract: OBJECTIVE: To determine the safety of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 (ICAM-1) (ISIS 2302), administered in an intensive 4 week regimen with dose escalation; and to provide preliminary evidence for efficacy in rheumatoid arthritis (RA). METHODS: Patients with active RA were enrolled in a 6 month, double blind, placebo controlled, dual center, dose escalation (0.5, 1, and 2 mg/kg) study. Subjects received a total of 13 intravenous ISIS 2302 infusions, given on alternate days for 2 weeks and then 3 times a week for another 2 weeks. Doses of corticosteroids (< or = 10 mg/day) and disease modifying antirheumatic drugs (stable > or = 3 months) remained constant throughout the study. The primary efficacy endpoint was the Day 26 Paulus index, with secondary evaluations at Months 2-6. RESULTS: A total of 43 patients were enrolled with 11, 10, 3, and 19 patients receiving placebo or 0.5, 1, or 2 mg/kg of ISIS 2302, respectively. There were no differences between groups after randomization and the mean baseline swollen joint count was 22.5. Pharmacokinetic studies revealed a T(1/2) of 63 min and first-order kinetics with slight dose dependency, suggesting a saturable clearance process, although no accumulation was noted with repeat dosing. The Paulus 20% responses at Day 26 were 20%, 0%, and 5% for patients treated with ISIS 2302 (0.5, 1, 2 mg/kg, respectively) and 36% with placebo. For Months 2-6, the average intent-to-treat Paulus 20% responses were 21.2% for ISIS 2302 and 12.6% for placebo. Only ISIS 2302 treated subjects (19%) achieved Paulus 50% responses. ISIS 2302 was well tolerated. An expected and transient mean activated partial thromboplastin time increase of roughly 7 s was observed at the highest dose (2 mg/kg), as were small and clinically insignificant increases in serum C3a levels. T/B cell immunophenotyping, recall antigen skin testing, and serum immunoglobulin levels revealed no significant immunosuppressive effects. CONCLUSION: This study shows that 13 ISIS 2302 infusions over 4 weeks are well tolerated in patients with active RA. Although significant efficacy was not evident at the primary endpoint (1 month), the study lacked sufficient power to draw any formal conclusions. We tested a 4-fold drug concentration range, which led to a lower area under the curve range than was therapeutic in a subsequent Crohn's disease trial. Any further evaluation of this well tolerated ICAM-1 antisense agent should therefore be conducted at higher dosing.

Mayo PR, Skeith K, Russell AS, Jamali F. · Faculty of Pharmacy and Pharmaceutical Sciences, and Division of Rheumatology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. · Br J Clin Pharmacol. · Pubmed #11136300 links to  free full text

Abstract: AIMS: Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. METHODS: Eight RA patients were age- and sex-matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin-6 (IL-6) and nitrite (NO2-) were measured in predose samples. RESULTS: IL-6 and NO2- concentrations were significantly increased in parallel with disease severity. Oral clearance of both S- and R-verapamil was significantly decreased by RA. While the unbound fraction of S- and R-verapamil decreased by 5 and 7-fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S-verapamil. AUC of norverapamil enantiomers was increased 2-3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. CONCLUSIONS: RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-inflammatory cytokines and/or NO.

Russell AS. · Dr. A.S. Russell, University of Alberta, 562 Heritage Medical Research Centre, Edmonton, Alberta T6G 2S2, Canada. E-mail: · J Rheumatol Suppl. · Pubmed #19509326 No free full text.

Abstract: Early diagnosis and treatment of rheumatoid arthritis (RA) are important in order to halt disease progression and joint destruction, and minimize loss of function. Individually, the disease modifying antirheumatic drugs have demonstrated similar efficacies in radiological and clinical outcomes. However, various combination therapies have been shown to improve therapeutic outcomes for patients who fail to respond adequately to monotherapy. With the introduction of the cytokine inhibitors and the development of newer biologic therapies, a number of treatment options are available for patients with RA. The efficacies of the various treatment strategies are reviewed.

Ling S, Lewanczuk RZ, Russell AS, Ihejirika B, Jamali F. · University of Alberta, Edmonton, Alberta, Canada. · J Clin Pharmacol. · Pubmed #19168802 No free full text.

Abstract: Active rheumatoid arthritis (RA), obesity, and old age are associated with reduced responsiveness to the calcium channel antagonist verapamil despite increased drug concentrations. The diminishing effect appears to be associated with the severity of inflammation. We examined pharmacodynamics and pharmacokinetics of verapamil in patients with controlled RA. Volunteers included RA patients in remission: 12 on infliximab, 8 on other antirheumatic therapy, and 12 healthy subjects. Verapamil plasma concentrations and selected inflammatory mediators as well as blood pressure and electrocardiographic parameters were recorded after a single 80-mg dose of verapamil. Inflammatory mediators were all below what is reported for active RA, confirming that RA was controlled. The tumor necrosis factor-alpha concentration, however, was significantly higher in the infliximab group compared with other groups and the literature value for active RA. No significant difference was observed between groups in terms of percentage prolongation of PR interval despite a trend toward a lower response in the RA groups, the mean plasma concentrations, and the total and unbound area under the curve of verapamil. However, the slope of the S-verapamil concentration-effect curve was steeper for controls compared with the RA patients. Remission from active disease appears to restore plasma protein levels and hepatic drug metabolism activity in patients with RA, resulting in relatively normal verapamil pharmacokinetics.

Russell A, Beresniak A, Bessette L, Haraoui B, Rahman P, Thorne C, Maclean R, Dupont D. · University of Alberta, Edmonton, Canada. · Clin Rheumatol. · Pubmed #19089488 No free full text.

Abstract: To assess the cost-effectiveness of abatacept compared to different biologic treatment strategies for moderate to severe rheumatoid arthritis based on current medical practices in Canada. A model was constructed to assess the cost-effectiveness of various biologic treatments over a 2-year time horizon, using two effectiveness endpoints: "low disease activity state" (LDAS) and "remission". Abatacept, as first biologic agent after an inadequate response to DMARDs, provides greater treatment success rate for achieving LDAS (29.4% versus 15.6%) and remission (14.8% versus 5.2%), and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p<0.001). Abatacept, as second biologic agent after an inadequate response to one anti-TNF agent, provides greater treatment success rate for achieving LDAS (17.1% versus 10.2%) and remission (7.4% versus 3.9%) and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p<0.001). Abatacept is a cost-effective strategy in patients with an inadequate response to DMARDs or to one anti-TNF agent.

Maksymowych WP, Mallon C, Morrow S, Shojania K, Olszynski WP, Wong RL, Sampalis J, Conner-Spady B. · Department of Medicine, University of Alberta, Canada. · Ann Rheum Dis. · Pubmed #18524792 No free full text.

Abstract: BACKGROUND: Enthesitis is a recommended core domain for assessment of ankylosing spondylitis (AS), but no measurement has yet been validated according to Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) criteria. OBJECTIVE: The purpose of this study was to seek to validate an enthesitis index for patients with AS according to OMERACT criteria. METHODS: An enthesitis index was validated in two AS patient cohorts: (1) a longitudinal cohort (n = 223) and (2) 22 patients from three Canadian sites participating in a 24-week randomised placebo-controlled trial of adalimumab in AS. Construct validity was evaluated by correlation analysis with the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI) and quality of life instruments. Reproducibility was assessed by intraclass correlation coefficient (ICC), and responsiveness was assessed by Guyatt's effect size and standardised response mean. RESULTS: The most frequently affected sites were the greater trochanter and supraspinatus insertion ( approximately 20%). Patients with enthesitis had significantly greater scores for the BASDAI, BASFI, patient global, AS-specific quality of life index (ASQOL) and the Short Form 36 (SF-36) General Health Survey (p<0.001). The enthesitis score contributed significantly to variance in the BASDAI and BASFI. Interobserver ICCs were 0.96 in the longitudinal cohort and 0.89 and 0.77 in the adalimumab clinical trial cohort (for status and change score, respectively). Significant differences in change scores were evident for all patients after 24 weeks of adalimumab treatment, (p = 0.04), this being more significant when a subset of the most commonly affected entheses were analysed (p = 0.01). CONCLUSION: AS patients with enthesitis constitute a more severe subset of disease, and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index is feasible and reliable for measurement of this condition. Discrimination requires further study in larger trials.

Maksymowych WP. · Heritage Medical Research Building, University of Alberta Edmonton, Alberta, Canada. · Ther Clin Risk Manag. · Pubmed #18516314 links to  free full text

Abstract: Non-steroidal anti-inflammatory agents (NSAIDs) remain the mainstay of treatment for ankylosing spondylitis (AS) though one recent trial suggests that continuous as opposed to on-demand use may be superior in preventing progression of structural damage. One particular NSAID, which is a highly selective cyclo-oxygenase 2 inhibitor, etoricoxib, may be superior to standard NSAIDs for AS. Second-line agents typically used for rheumatoid arthritis appear to lack efficacy. Salazopyrin is only moderately effective in the subgroup of AS patients with concomitant peripheral arthritis and not in those with purely axial disease. A recent trial showed that there is no greater efficacy in patients presenting early in their disease course. Three anti-tumor necrosis factor alpha agents, infliximab, etanercept, and adalimumab, are now available for the treatment of AS, the latest being adalimumab. All possess similar clinical efficacy in phase III trials with response rates of about 60%. Imaging studies using magnetic resonance show substantial amelioration of inflammatory lesions in the spine and sacroiliac joints. There is as yet no evidence that any of these agents prevent progression of structural damage. One study that evaluated etanercept demonstrated no impact on damage progression. Increasing evidence points to the superiority of the two monoclonal antibodies, infliximab and adalimumab, over etanercept for the treatment of extra-articular manifestations typically seen in AS such as acute anterior uveitis and inflammatory bowel disease. All three agents can be used as monotherapy and concomitant methotrexate appears to offer no advantages although insufficient doses have been used to date. Future studies should target patients earlier in their disease course as well as those with adverse prognostic factors such as elevated serum metalloproteinase 3 levels and radiographic evidence of spinal ankylosis.