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POSTERS
1 EXTREME HYPERFERRITINEMIA IN CHILDHOOD Jonathan Akikusa, Athimalaipet V Ramanan, Sheila Wietzman, Earl D Silverman, Rayfel Schneider (Division of Rheumatology The Hospital for Sick Children, Toronto, Canada, Division of Hematology/ Oncology The Hospital for Sick Children, Toronto, Canada) Background: Extreme hyperferritinemia is well described in hemophagocytic lymphohistiocytosis (HLH) in childhood. Recently there has been interest in the use of serum ferritin as a diagnostic marker of Macrophage Activation Syndrome (MAS), increasingly recognized as a form of HLH. At the present time the specificity of extreme hyperferritinemia for this disorder is unknown. Aim and Methods: To identify the diagnoses of all children with a serum ferritin of >5000 mcg/l managed at the Hospital for Sick Children between November 1996 - March 2003. Patients were identified by a laboratory database search based on serum ferritin levels and a retrospective chart review undertaken. Results: 80 children were identified of whom 38 were male. The median age of patients at the time of maximum recorded serum ferritin was 9.0 years (range: 1 day - 21.8 years). The median serum ferritin across all patients was 9076 mcg/l (range: 5084 - 165550 mcg/l). Median serum ferritin was highest in those with HLH, either primary or secondary to rheumatic diseases, infection or malignancy (22504 mcg/l). Of those without HLH median serum ferritin was highest in those with infection (19109 mcg/l) followed by rheumatic diseases (13933 mcg/l), liver disorders (7748 mcg/l), malignancy (7523 mcg/l) and other disorders including non-malignant haematological disease. Fifteen children had rheumatic diseases; systemic-onset JRA (SoJRA)(9), adult onset Stills disease (1), lupus (2) and Kawasaki disease (3). Children with rheumatic diseases associated with HLH had a median serum ferritin of 52010 mcg/l compared with 13933 mcg/l for those without HLH. Thirty-seven patients had a serum ferritin of >10,000 mcg/l of whom 18 had primary or secondary HLH (7 with rheumatic disease-associated MAS). Of the nineteen patients without evidence of HLH and a serum ferritin >10,000 mcg/l, 3 had active SoJRA. Conclusion: Extreme hyperferritinemia in children is associated with a number of diseases including HLH, active SoJRA without MAS, liver disease and infections. In our series, fewer than 50% of patients with a serum ferritin of greater than 10,000 mcg/l had a diagnosis of HLH. 2 'REAL-WORLD' EFFECTIVENESS OF INFLIXIMAB AND LEFLUNOMIDE: THE ALBERTA EXPERIENCE. Susan Barr, Walter Maksymowych, Whitney Steber, Catherine Mallon, Liam Martin (University of Calgary, University of Alberta) Background: While infliximab (INF) & leflunomide (LEF) appear to be safe & efficacious in randomized trials, their use in usual clinical practice (effectiveness) requires ongoing study given concerns about potential serious adverse effects (AE) & cost. Therefore, we prospectively studied AE & effectiveness of INF & LEF in a cohort of Albertans with ACR criteria for rheumatoid arthritis (RA). Methods: A convenience sample of RA pts from Calgary & Edmonton received INF 3 mg/kg IV every 8 wks (n=334) or leflunomide 20 mg/day (n=219) & were followed for up to 3 yrs. Dose adjustments & cointerventions occurred according to standard practice. Joint counts, pt & physician global scores, pain scales, HAQ, ESR, & SF-36 were assessed at weeks 0, 14, 54 & every 6 months thereafter. Results: Baseline characteristics of the INF & LEF groups were similar & disease activity was high in both groups (Table). All measures improved significantly (p<.05) at weeks 14 & 54 compared to baseline in both groups, except the ESR & SF36 mental scores did not improve in the LEF group. All measures improved to a greater extent in the INF group. Mean duration of followup was 47±44 (INF) & 22±23 mo (LEF). INF was stopped for nonefficacy in 15% after a mean of 27±28 mo, & LEF was stopped in 6% for nonefficacy after 18±12 mo; 24% discontinued drug due to AE after 14±16 mo (LEF) & 28+31 mo (INF). Serious AE occurred in 25 pts on INF (2 deaths) & 15 pts on LEF (3 deaths); cancer was diagnosed in 1 INF (lymphoma) & 2 LEF (larynx, anus) pts. In the INF group, new psoriatic skin lesions occurred in 6 pts & 3 developed drug-induced lupus.
Conclusions: LEF-treated pts have similar baseline characteristics to pts on INF & appear to be a good comparator group for pharmacovigilance studies of biologic agents. A greater improvement in disease activity was observed in the INF group. In both groups, AE requiring discontinuation occurred in one quarter of pts, while a larger proportion of INF (15%) than LEF (6%) pts stopped the drug due to lack of efficacy. The latter findings may be due to the shorter duration of followup in the LEF group. This work is being expanded into a provincial pharmacovigilance program to monitor long-term safety & cost-effectiveness of biologic agents.
3 PATIENT SATISFACTION IN AN AMBULATORY RHEUMATOLOGY CLINIC Mary Bell, Philippe Bedard (Division of Rheumatology, Department of Medicine, Sunnybrook & Women's College HSC, Toronto ON, Department of Medicine, University of Toronto, Toronto ON) Purpose To determine patient satisfaction with care in the Division of Rheumatology at Sunnybrook & Women's College HSC across six domains: provision of information, empathy with the patient, attitude towards the patient, access to and continuity with the caregiver, technical quality and competence, and general satisfaction. Methods Patients who had a diagnosis of chronic arthritis and had been seen in clinic on at least three prior occasions were asked to complete the Leeds Patient Satisfaction Questionnaire (LPSQ) once they had registered for their appointment. The LPSQ is a 45-item Likert scale (1-5; <3 - dissatisfied; >3 - satisfied) survey measuring satisfaction with care across the six domains described above. The attending rheumatologist and other clinic medical staff were not made aware of which patients had completed the questionnaire. All questionnaires were scored according to the guidelines of the Leeds Satisfaction Questionnaire, and were checked by two independent investigations to minimize arithmetical errors. Descriptive statistics were calculated. Results Eighty-seven patients completed the questionnaire. The mean normalized Overall Satisfaction score, combining satisfaction rates across all subgroups, was 4.19. The overall mean scores of the subgroups were: "Giving of information" - 4.25; "Empathy with the patient" - 4.25; "Technical quality and competence" - 4.63; "Attitude towards the patient" - 4.17; "Access to the service and continuity of care" - 4.00; "General Satisfaction" - 4.00. Conclusions Patients appear to be very satisfied with the care they receive. Areas that could be improved in the future include patient education regarding clinic services, waiting times, and receiving urgent consultation if needed. 4 INFECTIONS ASSOCIATED WITH ANTI-TNF ALPHA AGENTS Ching Sang Lee, Mary Bell (Division of Clinical Immunology and Allergy, Department of Medicine, University of Toronto, Toronto, Canada, Division of Rheumatology, Department of Medicine, Sunnybrook and Women's College HSC, University of Toronto, Toronto, Canada) Objective: To assess the risks of infection associated with anti-TNF agents. Methods: A literature review of the infectious risks of anti-TNF agents in animal models and humans. Results: TNF-alpha plays an important role in both the innate and adaptive immune response. Therefore, it is not unreasonable to assume that the use of anti-TNF agents would lead to diminished immunity. This is confirmed in animal models where an increased susceptibility to typical and atypical infectious agents is seen with both knock out animals and animals treated with anti-TNF agents. Although major human clinical trials have failed to show a significant difference between anti-TNF agents and placebo, post marketing surveillance has revealed an apparent increase in both typical and atypical infections in patients receiving these drugs. Mycobacterium tuberculosis has been the most prominent of these infections. In addition, patients may present with more severe or atypical disease. Conclusions: Anti-TNF alpha agents are associated with an increased risk of infection. Strategies that may reduce this risk would include: proper education of patients and physicians and prophylaxis where appropriate. All patients should have their standard vaccinations. As many patients on anti-TNF agents fit into an immunocompromised category, pneumococcal vaccination should be offered. 5 WILL RHEUMATOLOGISTS USE PERSONAL LEARNING PROJECTS AS A METHOD OF CONTINUING PROFESSIONAL DEVELOPMENT AND CERTIFICATION? Mary Bell, Gary Sibbald (Department of Medicine, University of Toronto) Purpose: To determine whether Rheumatologists adopt and adhere to the use of personal learning projects (PLPs) as a method of continuing professional development (CPD) and maintenance of certification following the introduction to the concept of PLPs and their utilization within a review workshop. Methods: Audience: 25 Ontario rheumatologists attending a 2 day continuing education workshop. Manoeuvre: A 30 minute interactive lecture was delivered outlining the concept of learning portfolios and demonstrating how to use a PLP for continuing education. Analysis: a. Descriptive statistics defined baseline participant demographics including age, gender, location of practice, years in rheumatology practice, type of practice. b. Baseline, Post-workshop, and 3 month follow-up qualitative data was analyzed using coding and theme definition identified by HyperResearch® software. c. Change scores were calculated on quantitative data collected at baseline, post-workshop, and 3 month follow-up. Results: Participants had been in Rheumatology for a mean of 16 years. 65% of the rheumatologists received their certification before the year 1991, with a similar number of males and females. Practitioners in the cities of Toronto and Ottawa were most commonly represented. Solo practices were 38.4% more common than group practice and the 3.8% practicing rurally were in solo practice. Greater than twice as many practiced only Rheumatology as compared to those practicing both Rheumatology and Internal Medicine. In 2002 the average number of PLPs was reported at 5.8 with a median of zero (range 0-120). Post workshop results indicated that the participants estimated that they would personally increase their PLPs in 2003 to an average of 13.6. The change in hours spent on PLPs was also predicted to increase from an average of 8.2 to 29.7. In the pre-workshop questionnaire, several participants indicated that they were uncertain of the benefits of the PLP method for CPD. Post-workshop results concluded that participants saw time as the number one constraint for their personal involvement with CPD; however, data showed a 7.7% decrease in the number of participants who had initially listed this factor as a deterrent. An analysis of post-workshop results showed that participants had listed 3 benefits to the PLP method for CPD review, despite not seeing any advantages in the pre-workshop. Such benefits including: a good way to gain credits, personalising learning, track new knowledge. Furthermore, there was an increase in the usage of different PLP methods of recording. The use of Paper Diaries was the favoured method of choice, followed by Other Means and Web Diaries. There was an apparent increase in the PLP method as opposed to other methods when participants were asked to quantify their CDP usage. Conclusion: We are presently awaiting the follow up results on the 3-month data for this project, and will have conclusions prepared for presentation at the CRA meeting. The data compiled from the 3-month follow up will provide a better prospective on the effectiveness of the workshop on Personal Learning Projects, and will illustrate whether or not the participants were able to follow through on their predicted goals. Supported by an unrestricted educational grant from Aventis Canada. 6 PRIMARY CNS VASCULITIS: PREDICTORS OF NEUROLOGIC OUTCOME Susanne M Benseler, Gabrielle DeVeber, Brian M Feldman, Rayfel Schneider, Richard I Aviv, Derek Armstrong, Pascal N Tyrrell, Laura M Tsang, Earl D Silverman (Divisions of Rheumatology, The Hospital for Sick Children, Toronto, Divisions of Neurology, The Hospital for Sick Children, Toronto, Divisions of Radiology, The Hospital for Sick Children, Toronto) Aim of study: To identify predictors of a persistent neurological deficit in children with primary CNS vasculitis. Methods: A single-center retrospective cohort study of children diagnosed with primary CNS vasculitis between 01/01/1990 and 31/12/2002 was performed. Exclusion criteria: a) neonates, b) significant underlying conditions. Inclusion criteria: angiography and/or brain biopsy demonstrated CNS vasculitis. Data: Clinical data were obtained in prospectively collected, standardized assessments at 0, 3, 6, 12 and 24 months follow up. Laboratory data were collected. All imaging studies (MR, MR/conventional angiography) were blindly analyzed by two radiologists. Outcome: Persistent neurological deficit >6months. Analysis: Univariate regression analysis of putative predictors. Results: 66 children (38M:28F) were included, mean age: 7.8yrs (range 0.7-17.6); mean follow up: 21.5 months (range 6.3-60). Treatment groups: Anticoagulation only (40/66), immunosuppression ± anticoagulation (26/66). Outcome: 41 children (62%) had a persistent neurological deficit. Predictors: Isolated stroke features at diagnosis (p=0.0034 OR 6.41 CI 1.71-14.01) and proximal, large vessel stenosis on angiography (p=0.002, OR 5.66, CI 1.66-19.24) were associated with a persistent neurological deficit. Neurocognitive dysfunction at diagnosis (p=0.04 OR 4.3, CI 1.21-8.62) and immunosuppressive therapy (p=0.03, OR 3.1, CI 1.1-8.67) were associated with neurological recovery. Conclusions: Clinical presentation, initial imaging results and treatment regimens predicted a persistent neurological deficit in children with primary CNS vasculitis. Large vessel CNS vasculitis presenting as isolated stroke and treated with anticoagulation only had the highest probability of a permanent neurological deficit. 7 INFLIXIMAB THERAPY OF REFRACTORY CHILDHOOD POLYARTRITIS NODOSA (PAN) Susanne M Benseler, Sandra Parker, Kristy Whitney Mahoney, Ronald M Laxer (Division of Rheumatology. The Hospital for Sick Children, Toronto) Aim of study: To describe a paediatric case of therapy-refractory PAN and to report the Infliximax treatment response. Material and methods: A prospective observational case study of a 12 year old boy with PAN was performed. Clinical presentation including disease activity, functional status (CHAQ), laboratory test results, treatment protocol and treatment side effects were collected in standardized sequential assessments. Summary of results: We report a 12 year old boy of Caribbean descent with disease duration of 11years. Height 114cm (<<3.P) and weight 22kg (<<3.P) indicated severe failure to thrive. Organ involvement: Liver (fibrosis plus Budd Chiari), kidneys (renal artery stenosis, hypertension), blood (anaemia), joints (polyarthritis), and skin (painful nodules). Previous treatment included: methotrexate (MTX) (PO and SC), azathioprine and cyclophosphamide (IV and PO). Steroid treatment was never discontinued due to persistent disease activity. He required at least 1 mg/kg/day for control of the painful skin nodules. Infliximab was started in 11/2002 at 5mg/kg every 4 weeks. Subjectively he improved rapidly, skin lesions healed while the steroid dose was slowly weaned. After 6 months of Infliximab, at 5mg/day of prednisone plus MTX he developed new ulcerative skin lesions. Investigation for infection was negative and the dose of Infliximab was increased to 10mg/kg per infusion. After 14 month of Infliximab therapy his overall well being is dramatically better reflected in a CHAQ disability index of 0.87 (11/02: 1.3), skin lesions have healed, the anaemia resolved, inflammatory markers settled (CRP 71 to 10.6mg/dl). Conclusions: Infliximab provides a save and effective therapeutic option for refractory PAN in childhood. Breakthrough of active disease may occur and may require dose adjustment. 8 PRIMARY CNS VASCULITIS IN CHILDREN: IDENTIFICATION OF A HIGH RISK COHORT Susanne M Benseler, Gabrielle DeVeber, Richard I Aviv, Derek Armstrong, Rayfel Schneider, Laura M Tsang, Pascal N Tyrrell, Earl D Silverman (Division of Rheumatology, The Hospital for Sick Children, Toronto, Division of Neurology, The Hospital for Sick Children, Toronto, Division of Radiology, The Hospital for Sick Children, Toronto) Objective: To identify criteria of children with primary CNS vasculitis at high risk for disease progression requiring immunosuppressive therapy. Methods: Single center retrospective cohort study of children diagnosed with primary CNS vasculitis between 01/01/1990 and 31/12/2002 was performed. Exclusion criteria: a) neonates, b) significant underlying conditions or known causes of vasculopathy and c) lack of imaging/biopsy. Inclusion criteria: conventional angiography (CA)/magnetic resonance (MR) angiogram (MRA) or brain biopsy demonstrated vasculitis. Definition: Progressive vasculitis was defined as progression of stenosis at >3months after initial angiography. Cohorts: I) Angiography-positive, non-progressive cohort (N=42), II) angiography-positive, progressive (N=20) and III) angiography-negative cohort (N=4). Data collection: Clinical data were obtained in prospectively collected, standardized assessments. Laboratory tests results were included when available. All imaging studies were blindly analyzed by two radiologists. Biopsies were re-analyzed by study neuropathologist. Results: 66 (38M:28F) had a diagnosis of primary CNS vasculitis. Mean age at diagnosis: 7.8 yrs (0.7-17.6 years). Patients in the angiography-positive, non-progressive disease cohort were more likely to present with a stroke (p=0.001), unifocal MR lesions and proximal large vessel stenoses on angiography. The progressive, angiography-positive cohort more commonly presented with neurocognitive dysfunction (p<0.001), headaches (p<0.001), multifocal (p=0.02) and/or bilateral MR lesions (p=0.05) and multiple (p=0.03), bilateral (p=0.0015) or peripheral stenoses (p=<0.001). Angiography-negative patients had similar clinical features at presentation and MR abnormalities as cohort II, however progressed more rapidly, had a normal angiography and small vessel vasculitis on brain biopsy. Conclusions: Three cohorts of children with primary CNS vasculitis can be defined based on clinical, radiographical and histological criteria. Patients with neurocognitive dysfunction and headaches, multifocal and/or bilateral MR lesions and multiple, bilateral and/or peripheral stenoses or vasculitis on brain biopsy determined a high risk profile of children requiring immunosuppressive therapy. 9 HYDROXYCHLOROQUINE IS ASSOCIATED WITH LOWER RISK OF THROMBOTIC EVENT IN A LONGITUDINAL OBSERVATIONAL COHORT. Raja Bobba, Zhaleh Shariati, Dominique Ibanez, Dafna Gladman, Murray Urowitz, Paul R. Fortin (Toronto Western Hospital, University Health Network, Toronto, Ontario) Objective: To evaluate if hydroxychloroquine (HCQ), azathioprine (AZA), prednisone or cyclophosphamide (CYCLO) are associated with lower occurrence of thrombotic events (TE) in systemic lupus erythematosus (SLE). Methods: Population: We reviewed prospectively collected data from 1021 patients of the University of Toronto lupus database (age 18 and over, 4 or more ACR criteria). Outcome variables: TE were defined by clinical, laboratory, radiological or pathologic criteria. Arterial TE was defined as the presence of cerebrovascular accident, transient ischemic attack, myocardial infarction, angina, peripheral vascular disease or other arterial events and venous TE as deep venous thrombosis, pulmonary embolus, or other venous events. Exposure variables: The exposures of interest are use of HCQ, AZA, prednisone and CYCLO (as dichotomous variables) prior to TE or until last visit in the database. Covariates: Age at diagnosis, sex, smoking, hypertension (HBP), diabetes mellitus (DM), oral contraceptive (OC) use in women, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) at first visit, and whether SLE diagnosis was made before or after 1990 (to account for differences in lupus treatment over time). Analysis: Risk factors between presence/absence of TE were compared using chi-square and t-tests. Cox proportional hazard multiple regressions using time to first TE as the outcome were conducted to assess if medication is a protective factor after adjusting for the covariates. Results: Of 1021 patients, 161 have had one or more TE. Bivariate analyses showed that female sex (p=0.007), higher age at SLE diagnosis (p<0.0001), HBP (p=0.0001), OC use in women (p=0.04), and year of SLE diagnosis before 1990 (p=0.0004) were associated with higher risk of TE. Patients with TE used HCQ less (26%) than those without TE (38%) (p= 0.002). AZA was used more in the TE group (37%) than in the non-TE group (29%) (p=0.03). Prednisone was used in 86% of the TE group and 77% of the non-TE group (p=0.03). CYCLO was used rarely and could not be further studied (6% vs 4%, p=0.36). HCQ model: HCQ had a protective effect (p=0.02) after adjusting for age at diagnosis, sex, SLEDAI-2K at presentation and smoking. AZA model: AZA was associated with higher risk of TE (p=0.02) after adjusting for sex, smoking and SLEDAI-2K at presentation. Prednisone model: Prednisone was not associated with TE after adjusting for sex, SLEDAI-2K, and smoking. Conclusion: HCQ may be a thromboprotective agent that merits further study in SLE. 10 AUTOANTIBODIES AS PROGNOSTIC MARKERS OF PERSISTENCE AND OF SEVERITY AT 18, 30 AND 42 MONTHS IN EARLY POLYARTHRITIS (EPA) PATIENTS. Gilles Boire, Pierre Cossette, Artur J. de Brum-Fernandes, David Hercelin, Patrick Liang, Daniel Myhal, Sophie Roux, Théophile Nyonsenga, Michel Gingras, Claude Daniel*, Julie Beauchemin, Isabelle Deschênes, Henri A. Ménard** (Centre hospitalier universitaire de Sherbrooke (CHUS), *Université du Québec, INRS-Institut Armand-Frappier, **McGill University) Consecutive adult patients presenting with synovitis affecting ≥ 3 joints for ≥ 1 and ≤ 12 months (EPA) were included in a longitudinal observational study and followed up at 18, 30, 42 and 60 months after disease onset. Patients were treated according to good clinical practice standards by physicians blinded to HLA-DR, anti-Sa/citrullinated vimentin and anti-Cyclic Citrullinated Peptide (CCP) Abs status. We present an interim analysis of 136 patients. At inclusion, mean age was 58 years, mean disease duration was 4.7 months, ≥ 4 ACR criteria for RA were present in 79%, IgM RF in 35%, anti-CCP (Inova Diagnostics) in 33%, anti-Sa in 23%, a Sharp/van der Heijde erosion score >5 in 33%, and RA-associated HLA epitopes in 70%. Pre-defined outcomes evaluated at 18, 30 and 42 months were:1) Persistence of arthritis, defined as ≥ 1 synovitis OR current use of DMARDs; 2) Current fulfillment of ≥ 4 ACR criteria for RA; and 3) Severe arthritis, defined as M-HAQ score ≥ 1.0 OR being in the upper tertile of the Sharp score (≥ 24, ≥ 27, ≥ 40 at 18, 30 and 42 months). Persistence of disease was found in 85%, 82% and 76% at each evaluation (with more than 50% without a single synovitis). A total of 22%, 18% and 21% met criteria for RA at 18, 30 and 42 months; 45%, 33% and 34% had Severe Disease defined as above at 18, 30 and 42 months. All 3 serological markers (RF, anti-Sa and anti-CCP) were good predictors for Persistence of arthritis at all 3 follow ups (Positive likelihood ratios (LR+) from 2 to 8). The single most significant predictor for meeting RA criteria and for Severe disease at 18, 30 and 42 months was anti-Sa at inclusion (LR+ of 2.3, 2.6, 2.2 and 2.4, 2.0, 17, respectively). In comparison, for the same outcomes of RA criteria and Severe disease, the presence of anti-CCP Abs yielded LR+ of 1.5, 1.9, 2.3 and 1.1, 1.3, 1.2, respectively. Anti-CCP was no better than RF (LR+ of 1.8, 2.0, 2.5 (possibly biased by unblinding to RF) and 1.3, 1.8, 1.6, respectively). At inclusion, no clinical or genetic marker predicted by univariate analysis any of the preset outcomes. DMARDs were used much more aggressively in anti-Sa (+) patients than in other patients with persistent arthritis. All assays for Abs to citrullinated antigens are not equivalent. In our EPA population, anti-CCP Abs performed no better than RF to predict poor outcome. On the contrary, anti-Sa Abs identified a subgroup of EPA patients likely to have more persistent arthritis, more joint damage, and more severe arthritis at 18 months, despite more aggressive use of DMARDs. Detection of anti-Sa Abs in EPA may be more useful than detection of RF or anti-CCP.
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