A Population-level Analysis of the Differing Effects of Rheumatoid Arthritis and Spondyloarthritis on Peripartum Outcomes.

OBJECTIVE: The effects of rheumatoid arthritis (RA) and spondyloarthritis (SpA) on maternal and neonatal outcomes at a population level have not previously been well compared. METHODS: A contemporary pregnancy cohort of 312,081 women and corresponding birth events was assembled for the province of Alberta from the random selection of 1 live birth event per woman. We identified 3 groups: (1) no inflammatory arthritis (no IA, n = 308,989), (2) RA (n = 631), and (3) SpA (n = 2461). We compared maternal and neonatal outcomes, comorbid conditions, and medication use among the 3 groups. Multivariable logistic regression models evaluated the independent association between RA and SpA, relative to no IA, and the outcomes of small for gestation age (SGA) and hypertensive disorders during pregnancy. RESULTS: Pregnant women with RA were significantly more likely to have preterm delivery (13.5%), cesarean delivery (33.9%), hypertensive disorders in pregnancy (10.5%), and SGA babies (15.6%), compared to pregnant women with either SpA or no IA. Nonsteroidal antiinflammatory drugs and corticosteroid use were significantly higher in pregnant women with RA compared to the other groups. Women with RA were significantly more likely to have an SGA baby (OR 1.51, 95% CI 1.21-1.88; p < 0.01), and hypertensive disorder in pregnancy (OR 1.51, 95% CI 1.16-1.97; p < 0.01), compared to women with no IA, while no difference was found between women with SpA and those with no IA. CONCLUSION: Women with RA have a higher risk of worse maternal and neonatal outcomes, whereas the risk of these events is similar between women with and without SpA.

Canadian Rheumatology Association Recommendations for the Assessment and Monitoring of Systemic Lupus Erythematosus.

OBJECTIVE: To develop recommendations for the assessment of people with systemic lupus erythematosus (SLE) in Canada. METHODS: Recommendations were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The Canadian SLE Working Group (panel of Canadian rheumatologists and a patient representative from Canadian Arthritis Patient Alliance) was created. Questions for recommendation development were identified based on the results of a previous survey of SLE practice patterns of members of the Canadian Rheumatology Association. Systematic literature reviews of randomized trials and observational studies were conducted. Evidence to Decision tables were prepared and presented to the panel at 2 face-to-face meetings and online. RESULTS: There are 15 recommendations for assessing and monitoring SLE, with varying applicability to adult and pediatric patients. Three recommendations focus on diagnosis, disease activity, and damage assessment, suggesting the use of a validated disease activity score per visit and annual damage score. Strong recommendations were made for cardiovascular risk assessment and measuring anti-Ro and anti-La antibodies in the peripartum period and conditional recommendations for osteoporosis and osteonecrosis. Two conditional recommendations were made for peripartum assessments, 1 for cervical cancer screening and 2 for hepatitis B and C screening. A strong recommendation was made for annual influenza vaccination. CONCLUSION: These are considered the first guidelines using the GRADE method for the monitoring of SLE. Existing evidence is largely of low to moderate quality, resulting in more conditional than strong recommendations. Additional rigorous studies and special attention to pediatric SLE populations and patient preferences are needed.

Measuring Disease Activity and Damage with Validated Metrics: A Systematic Review on Mortality and Damage in Systemic Lupus Erythematosus.

OBJECTIVE: To identify the effect of disease activity and damage, measured by validated indices, on mortality and damage accrual, in order to inform upcoming Canadian systemic lupus erythematosus (SLE) recommendations. METHODS: Following GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology to fill in evidence-to-decision tables to create recommendations for "minimal investigations needed to monitor SLE patients at baseline and subsequent visits," a systematic literature review was performed. The effect of disease activity and damage, measured by validated metrics, on mortality and damage was systematically reviewed, with metaanalyses performed when available. RESULTS: A title/abstract screen of 5599 articles identified 816 articles for full paper review, with 102 meeting inclusion criteria and 53 with extractable data. Thirty-three articles describing outcomes related to disease activity and 20 articles related to damage were identified. Mortality was associated with higher SLE Disease Activity Index-2000 scores in 6 studies (HR 1.14, 95% CI 1.06-1.22) and higher Systemic Lupus International Collaborating Clinics/ACR Damage Index scores in 6 studies (HR 1.53, 95% CI 1.28-1.83). Higher SLE Activity Measure scores were associated with increased risk of damage in 3 studies (OR 1.06, 95% CI 1.04-1.08). British Isles Lupus Assessment Group was associated with mortality in 1 study with HR of 1.15. CONCLUSION: Active SLE disease and damage are associated with and predict greater mortality and damage. The use of validated disease activity and damage metrics is important in the assessment of disease activity and damage and will inform upcoming Canadian recommendations for the assessment of SLE.

Practice Variations in the Diagnosis, Monitoring, and Treatment of Systemic Lupus Erythematosus in Canada.

OBJECTIVE: To evaluate the diagnosis, monitoring, and treatment of systemic lupus erythematosus (SLE) in Canada. METHODS: A 63-question electronic survey was developed with the Canadian Rheumatology Association and others. Descriptive analyses of responses were performed. RESULTS: Survey respondents (n = 175) reported varying practices in the diagnosis, monitoring, and treatment of SLE. Performance of laboratory investigations for diagnosis and monitoring varied, with 78% of responders performing them at least every 6 months. Validated measures of SLE disease activity and damage were not commonly used. Most common first-line agents besides steroids for induction therapy for class III or IV lupus nephritis included intravenous cyclophosphamide and mycophenolate mofetil. Antimalarial use was common, with 96% of respondents using these in active skin disease. Over 60% of respondents indicated that 80-100% of their patients were taking antimalarials, while another 25% indicated they used these drugs in up to 80% of their patients. There were 71% of responders who reported completing frequent (6-12 mos) ophthalmology screening in patients taking antimalarials. Biologics were infrequently used. Responders were more likely to stop azathioprine and chloroquine than hydroxychloroquine in pregnant patients with SLE. Other aspects of routine care including vaccination and cardiovascular risk management varied considerably. The majority (80%) agreed that a dedicated multidisciplinary care team would improve SLE care. CONCLUSION: Considerable practice variation in SLE management was noted. This may help inform future recommendations for the diagnosis, monitoring, and treatment of SLE in Canada.

Subcutaneous belimumab in the treatment of systemic lupus erythematosus.

Systemic lupus erythematosus is a chronic autoimmune disease with various clinical manifestations, organ involvement and laboratory findings. The disease can involve any organ including skin, joints, kidneys, central and peripheral nervous system, cardiovascular system and more. Currently, the cornerstone of treatment includes antimalarial and immunosuppressive medications and glucocorticosteroids. Recently, great effort has been invested in finding more targeted drugs for achieving better control of the disease with less adverse events. Intravenous belimumab was the first and only biologic drug to be approved by the US FDA and Health Canada for lupus over the last 50 years, and recently was studied in subcutaneous form. This paper will review the major belimumab trials with a focus on the subcutaneous form.

Clinical effectiveness and safety of leflunomide in inflammatory arthritis: a report from the RAPPORT database with supporting patient survey.

Leflunomide is indicated for the treatment of adults with rheumatoid arthritis, yet is underutilized. Given the cost of biologic therapy, understanding real-life effectiveness, safety, and sustainability of leflunomide, particularly in patients who have failed methotrexate, would be of value. The primary objective was to assess the proportion of patients achieving clinically meaningful benefit following an adequate trial of leflunomide. A retrospective analysis of a cohort supplemented with patient self-reported data using a standardized questionnaire. Data were analyzed using descriptive statistics, with a database multivariate logistic regression analysis to determine predictors of leflunomide response. Of the cohort available (N = 2591), 1671 patients with confirmed leflunomide use were included in the retrospective analysis, of whom 249 were incident users. Low disease activity (DAS-28 < 3.2) was achieved or maintained by 20% of incident users, with 19% achieving a clinical response (DAS-28 decrease ≥1.2) at 3 months. Adverse effects (AE) were reported by 29% of incident users and after 1 year, 45% remained on leflunomide. Achievement of "minimal or no joint symptoms" was reported by 34% in the 661 analyzable survey responses (39% response rate). AE were reported by 55%, with nuisance (hair loss, nausea, stomach pain) AE and diarrhea being most common. Leflunomide was discontinued by 67% of responders within 1 year. An important proportion of patients, the majority of whom had previously failed methotrexate, achieved disease response with leflunomide with a low risk of serious adverse effects, suggesting that a trial of leflunomide may be a reasonable and cost-effective strategy prior to biologic therapy.

Preliminary validation of a self-reported screening questionnaire for inflammatory back pain.

OBJECTIVE: Inflammatory back pain (IBP) is an important feature of axial spondyloarthritis (SpA) that is poorly recognized in primary care, perhaps delaying diagnosis of SpA. We aimed to develop and validate a self-report questionnaire using important domains reported by patients with IBP. METHODS: We developed a 6-item questionnaire assessing spinal/hip stiffness, nocturnal pain, diurnal variation, effects of exercise/rest, and peripheral joint pain/swelling. This was compared with the Calin questionnaire and the domains comprising the Assessment of Spondyloarthritis International Society (ASAS) criteria for IBP in 220 patients with established axial SpA and 66 patients with mechanical back pain followed in tertiary care rheumatology clinics. The classification utility of each item was evaluated using sensitivity, specificity, and likelihood ratio (LR). Multivariable logistic regression was used to analyze different combinations of items to develop candidate scoring systems. RESULTS: The single item "diurnal variation" had the highest combination of sensitivity (49%) and specificity (92%) for IBP (positive LR 5.95, 95% CI 2.54-13.94), outperforming the Calin and ASAS IBP criteria, which had sensitivities of 83% and 59%, specificities 42% and 66%, positive LR 1.42 and 1.72, negative LR 0.41 and 0.62, respectively. Classification utility of this item was even higher in SpA patients with disease duration < 6 years (sensitivity 48%, specificity 96%, positive LR 12, negative LR 0.54). The other 5 items did not improve classification utility in any combination. CONCLUSION: Assessment of a single self-reported item, "diurnal variation," had substantial classification utility for IBP. This domain is not addressed in existing criteria for IBP, indicating a potentially important omission.

Lack of cardiovascular risk assessment in inflammatory arthritis and systemic lupus erythematosus patients at a tertiary care center.

The purpose of this study is to evaluate cardiovascular risk assessment at a Canadian rheumatology center and describe the cardiovascular risk of inflammatory arthritis (IA) and systemic lupus erythematosus (SLE) patients using the Framingham risk score. A retrospective chart review of 504 patients attending nine rheumatology practices at the University of Alberta Hospital was performed. A pre-specified case report form detailed patient demographics, cardiac risk factors, variables for the Framingham 2008 score, disease activity, and medication use. In this group of 504 patients, 64 (12.7%) had SLE (male (M) to female (F) ratio = 60:4) and 440 (87.3%) had an IA (M to F ratio = 117:323). Of the SLE patients, 31 (48.4%) met four or more American College of Rheumatology (ACR) criteria, 33 (51.6%) had less than four ACR criteria. Of the IA patients, 156 (35.5%) were CCP positive and 257 (58.4%) were RF positive. Utilizing the chart data, retrospective Framingham risk scores were calculable for one (1.6%) SLE patient and three (0.68%) IA patients. The most common cardiac risk factors not documented in the medical records of both the SLE and IA patients included: (1) positive family history of MI, (2) diabetes, and (3) lipid status. The blood pressure was more frequently documented in the SLE patients (93.8%) compared to the IA patients (56.1%). While traditional cardiac risk factors only partially contribute to the increased cardiovascular risk in these patients, cardiovascular risk assessment was suboptimally performed amongst a large group of rheumatologists. A dedicated cardiovascular risk reduction clinic for inflammatory rheumatic diseases has been established at this site to fulfill this need and evaluate treatment strategies.

Pregnancy and rheumatic disease: "by the book" or "by the doc".

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.

Testing of the preliminary OMERACT validation criteria for a biomarker to be regarded as reflecting structural damage endpoints in rheumatoid arthritis clinical trials: the example of C-reactive protein.

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.