M.C. van der Goes

Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice

Objective To develop recommendations on monitoring for adverse events (AEs) of low-dose glucocorticoid (GC) therapy (≤7.5 mg prednisone or equivalent daily) in clinical trials and daily practice. Methods Literature was searched for articles containing information on incidence and monitoring of GC-related AEs using PubMed, EMBASE and Cochrane databases. Second, the authors searched for broad accepted guidelines on the monitoring of certain AEs (eg, WHO guidelines on screening for diabetes). Available data were summarised and discussed among experts (rheumatologists and patients) of the EULAR Task Force to decide which potential AEs should be monitored, how and at which interval. Results Data on monitoring proved to be scarce; most articles were focused on therapeutic effects of GCs, not on occurrence and monitoring of AEs. Most recommendations had to be based on consensus. Those for clinical trials aimed at getting insights into incidence, prevalence and clinical relevance of AEs to create a comprehensive and valid AE-profile of GC therapy. The set of AEs to monitor is therefore more extensive, and often consists of assessments at baseline and at end of trials. Recommendations for daily practice are meant to protect patients from real dangers, which can be prevented or treated. Standard care monitoring needs NOT be extended for patients on low-dose GC therapy, except for osteoporosis (follow national guidelines), and baseline assessments of ankle edema, fasting blood glucose and risk factors for glaucoma. Conclusion Given the incompleteness of literature data, consensus-based recommendations on monitoring for GC-related AEs were created, separately for daily practice and clinical trials.

EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases

To develop recommendations for the management of medium to high-dose (ie, >7.5 mg but ≤100 mg prednisone equivalent daily) systemic glucocorticoid (GC) therapy in rheumatic diseases. A multidisciplinary EULAR task force was formed, including rheumatic patients. After discussing the results of a general initial search on risks of GC therapy, each participant contributed 10 propositions on key clinical topics concerning the safe use of medium to high-dose GCs. The final recommendations were selected via a Delphi consensus approach. A systematic literature search of PubMed, EMBASE and Cochrane Library was used to identify evidence concerning each of the propositions. The strength of recommendation was given according to research evidence, clinical expertise and patient preference. The 10 propositions regarded patient education and informing general practitioners, preventive measures for osteoporosis, optimal GC starting dosages, risk-benefit ratio of GC treatment, GC sparing therapy, screening for comorbidity, and monitoring for adverse effects. In general, evidence supporting the recommendations proved to be surprisingly weak. One of the recommendations was rejected, because of conflicting literature data. Nine final recommendations for the management of medium to high-dose systemic GC therapy in rheumatic diseases were selected and evaluated with their strengths of recommendations. Robust evidence was often lacking; a research agenda was created.

Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases

Objective To explore perspectives among patients and rheumatologists on glucocorticoid (GC) therapy and European League Against Rheumatism (EULAR) recommendations on the management of systemic GC therapy in order to enhance implementation of the recommendations. Methods Rheumatologists (from eight countries) and patients (from five countries) acquainted with GCs participated in separate meetings, during which positive and negative aspects of GC therapy were discussed and possible adverse events (AEs) were ranked for importance; in addition participants were asked to evaluate the published EULAR recommendations. The reports from these meetings and themes related to implementation of the recommendations were discussed during an international forum of the experts who had formulated the recommendations and patient participants. Results In all, 140 patients (78% women; mean age 53 years; 61% patients with rheumatoid arthritis) and 110 rheumatologists (mean work experience 15 years) participated in the meetings. Osteoporosis, diabetes and cardiovascular diseases were ranked among the five most worrisome AEs by patients and rheumatologists. In both groups, there was agreement with most of the recommendations; the recommendations on GC information cards and GC use during pregnancy scored lowest. Ideas to improve implementation of the recommendations and a research agenda were generated. Conclusion The patient and rheumatologist views on GCs corresponded to a large extent, reflected by concerns in both groups about osteoporosis, diabetes and cardiovascular diseases. Specific problems with the EULAR recommendations were identified and addressed to improve their implementation. This exercise shows that patient and rheumatologist perspectives should be included early in the process of formulating recommendations.

Glucose tolerance, insulin sensitivity and β-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids

Objectives To compare glucose tolerance and parameters of insulin sensitivity and β-cell function between chronic glucocorticoid (GC)-using and GC-naive patients with rheumatoid arthritis (RA). Methods Frequently sampled 75 g oral glucose tolerance tests were performed in 58 chronic GC-using and 82 GC-naive patients with RA with established disease, with no known type 2 diabetes mellitus (T2DM), and 50 control subjects of comparable age with normal glucose tolerance. The associations between cumulative GC dose and disease characteristics and glucose tolerance state, insulin sensitivity and β-cell function were tested using multivariate linear and logistic regression models, correcting for patient characteristics. Results Glucose tolerance state, insulin sensitivity and β-cell function did not differ between the two RA populations; de novo T2DM was detected in 11% and impaired glucose metabolism in 35% of patients with RA. In patients with RA, cumulative GC dose was associated with T2DM, which seemed mostly driven by the effects of cumulative GC dose on insulin resistance; however, the association decreased when corrected for current disease activity. Patients with RA had decreased insulin sensitivity and impaired β-cell function compared with controls, and multivariate regression analyses showed a negative association between the presence of RA and insulin sensitivity. Conclusions GC-using and GC-naive patients with RA had comparable metabolic parameters, and had decreased insulin sensitivity and β-cell function as compared with healthy controls. Although cumulative GC dose was shown to have a negative impact on glucose tolerance state and insulin sensitivity, confounding by indication remains the main challenge in this cross-sectional analysis.

Can adverse effects of glucocorticoid therapy be prevented and treated

Glucocorticoids are frequently used in the treatment of autoimmune inflammatory diseases and vasculitis. In the United States, the estimated prevalence of use is 1.2% in the general population [1], despite the fear for adverse effects [2]. These may indeed occur, but their severity is highly variable. Glucocorticoid-induced adverse effects differ according to duration of therapy and dosages used [3,4]. Although most studies are focused on therapeutic efficacy instead of adverse effects, the impression is that low-dose glucocorticoid therapy (i.e. ≤7.5 mg/day prednisone or equivalent) is relatively safe [5–7]. A recent literature search and expert consultation on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycemia/diabetes mellitus, cardiovascular diseases, and infections) showed that the level of harm of glucocorticoids depends on duration, dose, and patient-specific factors and that the risk of harm is low for the majority of patients on long-term treatment with dosages of ≤5 mg prednisone equivalent per day [7]. However, fear and uncertainty persist among patients and rheumatologists [2] since adverse effects are often not systematically assessed in trials and because it is not appreciated that adverse events are related to high dosages or long duration of treatment. Another reason is the difficulty of discriminating glucocorticoid-induced side effects from negative effects and complications of the disease (e.g. is a decrease in bone mineral density (BMD) caused by active rheumatoid arthritis, and/or is it an adverse effect of glucocorticoids?; see Figure 1). In this respect, also confounding by indication is important, i.e. patients with more severe disease are more likely to receive (higher actual and cumulative doses of) glucocorticoids. So, not all negative effects and events in patients on glucocorticoid therapy are definitely glucocorticoid-induced adverse effects, but some irrefutably are. Fortunately, some of these can be prevented or treated. Adverse effects that can be influenced by medication are listed in Table 1. In this review, we will discuss the drugs used in the prevention and treatment of glucocorticoid-related adverse effects. In addition, we will point out several general measures which can prevent these adverse effects.

SAT0217 Long Term Effects of Glucocorticoid Therapy on Radiological Progression of Joint Damage in Rheumatoid Arthritis: An Individual Patient Meta-Analysis

Objectives To determine the long term effects of initial glucocorticoid therapy on joint damage in patients with early rheumatoid arthritis (RA). Methods Randomised controlled trials assessing the efficacy of glucocorticoid treatment during one or two years in RA including follow up measurements after the original study duration were identified. Lead authors of these studies were invited to provide data on patient characteristics, disease activity, co treatment, and (erosive) joint damage. A comprehensive dataset with individual patient data was created and used for analyses, and data up to five years after the start of trials was analysed. Results Original study data and follow up measurements after the trial duration were shared by authors from five studies. Of the 838 patients entering these studies, 413 had been allocated to a treatment strategy including glucocorticoids. In total, 79% percent of the patients had at least one follow up radiograph scored between 3 and 5 years follow up after start of the original trial. Radiological progression over five years was significantly lower in glucocorticoid users (p=0.001). When analysing exclusively the time period after trials, initial glucocorticoid users and controls showed similar radiological progression rates.Table 1 Dependent variable: percentage of maximal radiological Model 1 Model 2 damage score over time (n=637; 3103 radiographs) (n=600; 2926 radiographs) Beta (95% CI) p-value Beta (95% CI) p-value Intercept 0.20 (−0.15 to 0.54) 0.26 1.17 (−0.35 to 2.68) 0.13 Baseline radiological score (percentage of maximal) 1.08 (0.89 to 1.27) <0.001 0.99 (0.84 to 1.13) <0.001 Treatment incl. predniso(lo)ne −0.30 (−0.53 to −0.07) 0.01 −0.30 (−0.63 to 0.02) 0.07 Time in months 0.09 (0.07 to 0.10) <0.001 0.09 (0.07 to 0.11) <0.001 Treatment incl. predniso(lo)ne * time in months −0.03 (−0.05 to −0.01) 0.001 −0.03 (−0.05 to −0.01) <0.01 Male gender −0.05 (−0.51 to 0.40) 0.83 Age in years 0.01 (−0.01 to 0.03) 0.44 RF positive 0.85 (0.45 to 1.25) <0.001 Study  ARC study −1.21 (−2.63 to 0.21) 0.10  BARFOT study −2.44 (−3.46 to −1.43) <0.001  CAMERA study −3.55 (−4.58 to −2.52) <0.001  COBRA study −0.18 (−1.32 to 0.96) 0.76  UTRECHT study reference study – This table shows the influence of initial treatment including predniso(lo)ne on radiological joint damage with correction for baseline radiological joint damage in model 1, and additional correction for gender, age, RF status and study in model 2. The significant negative beta of “treatment incl. predniso(lo)ne * time in months” indicates decreased progression over time in the group who used predniso(lo)ne during the trials. Progression of joint damage was most in the UTRECHT study (used as reference study); the CAMERA study showed least progression. CI = confidence interval; RF = rheumatoid factor. Conclusions Addition of glucocorticoid therapy to treatment in early RA is effective in decreasing radiological damage. This beneficial effect can still be identified after five years of follow up, mainly reflecting the initially obtained advantage. Disclosure of Interest None declared

SAT0051 Alternative Ways to Analyze Remission: Applying the Conrew Score and Patient Vector Graph to Camera –Trial II Data

Background In the two-year Computer Assisted Management in Early Rheumatoid Arthritis-trial II (CAMERA-II) (1), patients with early rheumatoid arthritis were randomized to a methotrexate (MTX-) based tight control strategy with either an additional 10mg/d prednisone (MTX+pred) or placebo (MTX+plac) from start. Until the first sustained (≥3 months) period of remission, time (in months (SD)) was shorter in the MTX+pred group than in the MTX+plac group (6 (5) vs.11 (5) resp., p<0.001). In the MTX+pred group more patients achieved at least one period of sustained remission, although not significantly different (72% vs. 61%, p=0.09). There is a need for methods to additionally describe both the duration of remission as well as the interruptions in this desired state that is simple to use. The continuity rewarded (“ConRew”) score and patient vector graph were developed with that in mind.(2) Objectives Posthoc analysis of the the CAMERA-II remission data in two alternative ways as compared to a simple sum score. Methods All 236 patients of the CAMERA-II trial (MTX+pred n=117, MTX+plac n=119) were studied to calculate their individual scores. Remission was defined as a swollen joint count of 0 (range 0-38 joints), and at least 2 of the following factors: tender joint count ≤3 (range 0-38 joints), VAS score ≤20mm and ESR ≤20mm/h. Remission was evaluated in one-month time periods. The ConRew score was calculated as follows: for every patient it counts (as points) the number of remission periods of a predefined length, adding a point for every period that is directly followed by another period in remission or for being in remission at the end of the observation period. To study the additional effect of continuity rewarding, a sum score was calculated by adding the number of remission periods. The visual pattern of remission periods in both groups were compared through patient vector graphs. Results The mean (SD) ConRew score differed statistically significantly (22.6 (15.7) vs.17.1 (13.9), p=0.004) between the two strategy arms in favour of the MTX+pred group. The mean (SD) plain sum score, in favour of the MTX+pred group, did not differ significantly (13.3 (8.1) vs. 11.3 (7.1), p=0.051). Effect size of the strategy arms measured through ConRew was larger than the effect size measured through the sum score (Cohens d=0.374 vs. Cohens d=0.255). The MTX+pred strategy led to a pattern of more and longer periods of remission in the patient vector graphs. Conclusions There is a significant difference in sustained remission between the two treatment arms, favouring MTX+pred. Although both the effect size values are in the small to medium range, the fact that the ConRew effect size is almost 1.5 times larger shows a more sensitive way of addressing sustained remission. The ConRew score and the patient vector graph appeared to be good alternatives to the sustained remission variable in CAMERA-II. References Bakker MF et al. Low-dose prednisone inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis. A Randomized Trial. Ann Intern Med 2012;156:329-39. Boers M et al. A new graph and scoring system simplified analysis of changing states: disease remissions in a rheumatoid arthritis clinical trial. J Clin Epidemiol 2010;63:633-7. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2589