A. van Tubergen

Assessment of enthesitis in ankylosing spondylitis

Objective: To assess, firstly, the validity of the enthesis index published by Mander (Mander enthesis index (MEI)) and, secondly, to investigate whether it is possible to define a new enthesis index that is less time consuming to perform with at least similar or better properties. Methods: Data from the OASIS cohort, an international, longitudinal, observational study on outcome in ankylosing spondylitis, were used. In this study, measures of disease activity, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the MEI, were assessed regularly in 217 patients. With the MEI, for each measurement period independently, a process of data reduction was performed to identify the entheses most commonly reported as painful by the patients. A more concise enthesis index was constructed with aid of the entheses found in this way. Correlations with measures of disease activity were used to test the validity of several entheses indices. Results: Reduction of the number of entheses from 66 to 13 and omitting grading of the intensity of pain resulted in an index which was named the “Maastricht Ankylosing Spondylitis Enthesitis Score” (MASES). The MASES (range 0–13) has much greater feasibility than the MEI (range 0–90). However, up to 21% of patients with a score >0 on the MEI were not identified by a score on the MASES >0. Only 2.1% of the patients with an original enthesis score >0 had an original score on the MEI >3 (range 0–90) and it can be questioned whether a low score on the MEI index represents clinically important enthesitis. The Spearman correlation coefficient between the MASES score and the MEI was 0.90 and between the MASES and the BASDAI was 0.53 compared with a correlation of 0.59 between the MEI and the BASDAI. Conclusions: MASES seems to be a good alternative to the MEI with much better feasibility.

Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality?

Objective: To assess performance of radiologists and rheumatologists in detecting sacroiliitis Methods: 100 rheumatologists and 23 radiologists participated. One set of films was used for each assessment, another for training, and the third for confidence judgment. Films of HLA-B27+ patients with AS were used to assess sensitivity. For specificity films of healthy HLA-B27− relatives were included. Plain sacroiliac (SI) films with simultaneously taken computed tomographic scans (CTs) were used for confidence judgment. Three months after reading the training set, sensitivity and specificity assessments were repeated. Next, participants attended a workshop. They also rated 26 SI radiographs and 26 CTs for their trust in each judgment. Three months later final assessments were done. Results: Sensitivity (84.3%/79.8%) and specificity (70.6%/74.7%) for radiologists and rheumatologists were comparable. Rheumatologists showed 6.3% decrease in sensitivity after self education (p=0.001), but 3.0% better specificity (p=0.008). The decrease in sensitivity reversed after the workshop. Difference in sensitivity three months after the workshop and baseline was only 0.5%. Sensitivity <50% occurred in 13% of participants. Only a few participants showed changes of >5% in both sensitivity and specificity. Intraobserver agreement for sacroiliitis grade 1 or 2 ranged from 65% to 100%. Sensitivity for CT (86%) was higher than for plain films (72%) (p<0.001) with the same specificity (84%). Confidence ratings for correctly diagnosing presence (7.7) or absence (8.3) of sacroiliitis were somewhat higher than incorrectly diagnosing the presence (6.6) or absence (7.4) of sacroiliitis (p<0.001). Conclusion: Radiologists and rheumatologists show modest sensitivity and specificity for sacroiliitis and sizeable intraobserver variation. Overall, neither individual training nor workshops improved performance.

Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis

OBJECTIVES Uveitis, psoriasis and inflammatory bowel disease (IBD) are common extra-articular manifestations (EAM) in patients with ankylosing spondylitis (AS); however, summary data of reported prevalence are lacking. The aim of the present study was to summarise the prevalence of EAMs among patients with AS and to identify underlying factors to explain potential heterogeneity of prevalence. METHODS A systematic literature search was performed (Medline, Embase and Cochrane Library) to identify relevant articles. Risk of bias was assessed and data were extracted. Pooled prevalences were calculated. Potential sources of any observed clinical or methodological heterogeneity in the estimates were explored by subgroup and metaregression analysis. RESULTS In the 156 selected articles, 143 reported the prevalence of uveitis (44 372 patients), 56 of psoriasis (27 626 patients) and 69 of IBD (30 410 patients). Substantial heterogeneity was observed in prevalence estimates among all EAMs (I(2)=84-95%). The pooled prevalence of uveitis was 25.8% (95% CI 24.1% to 27.6%), and was positively associated in multivariable metaregression with disease duration (β 0.05, 95% CI 0.03 to 0.08) and random selection of patients (β -0.24, 95% CI -0.43 to -0.04). The pooled prevalence of psoriasis was 9.3% (95% CI 8.1% to 10.6%). The pooled prevalence of IBD was 6.8% (95% CI 6.1% to 7.7%) and was positively associated with the percentage of women in the studies (β 0.02, 95% CI 0.00 to 0.03). Geographical area was associated in multivariable metaregressions with prevalence of all EAMs. CONCLUSIONS EAMs are common in patients with AS. The large heterogeneity between studies can be partly explained by differences in clinical as well as methodological characteristics.

Assessment of disability with the World Health Organisation Disability Assessment Schedule II in patients with ankylosing spondylitis

Objective: To investigate in ankylosing spondylitis (AS) whether the newly developed World Health Organisation Disability Assessment Schedule II (WHODAS II) is a useful instrument for measuring disability, to assess its responsiveness in relation to other traditional disease specific instruments, and to identify factors that are associated with both short term and long term scores on the WHODAS II. Methods: Patients with AS from a randomised controlled trial assessing the efficacy of spa treatment (n=117) and from a five year longitudinal observational study (n=97) participated. The patients completed several questionnaires, including the WHODAS II. After a three week course of spa treatment, 31 patients again completed all questionnaires to assess responsiveness. To determine to what degree the WHODAS II reflects some AS oriented measures on disease activity, functioning, and quality of life, correlation coefficients between the WHODAS II and these other questionnaires were calculated. Responsiveness was calculated by the effect size (ES) and standardised response mean (SRM). Linear regression analysis was performed to explore which factors might be associated with short term changes on the WHODAS II and to investigate (in the observational study) which factors of WHODAS II might predict disability five years later. Results: Mean score on the WHODAS II was 23.9 (SD 15.5 (range 0.0−76.1)). Scores on the WHODAS II were significantly correlated with all disease specific questionnaires measured (all p<0.001). The WHODAS II showed a comparable short term responsiveness score (SRM 0.41; ES 0.39). In regression analysis these short term changes on the WHODAS II were significantly associated with changes in functioning (β coefficient 4.25, 95% confidence interval (95% CI) 1.24 to 7.26, p=0.007). In the observational study, disease activity (β coefficient 0.35, 95% CI 0.17 to 0.53, p<0.000) as well as functioning (β coefficient 0.23, 95% CI 0.09 to 0.38, p=0.002) seemed to significantly predict disability (WHODAS II) after five years. Conclusion: The WHODAS II is a useful instrument for measuring disability in AS in that it accurately reflects disease specific instruments and that it shows similar responsiveness scores. In AS, a short term change on the WHODAS II is associated with a change in physical function. At the group level, disease activity and physical functioning may predict disability after five years.

Comparison of statistically derived ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel

Objective: To investigate whether the recently developed (statistically derived) “ASsessment in Ankylosing Spondylitis Working Group” improvement criteria (ASAS-IC) for ankylosing spondylitis (AS) reflect clinically relevant improvement according to the opinion of an expert panel. Methods: The ASAS-IC consist of four domains: physical function, spinal pain, patient global assessment, and inflammation. Scores on these four domains of 55 patients with AS, who had participated in a non-steroidal anti-inflammatory drug efficacy trial, were presented to an international expert panel (consisting of patients with AS and members of the ASAS Working Group) in a three round Delphi exercise. The number of (non-)responders according to the ASAS-IC was compared with the final consensus of the experts. The most important domains in the opinion of the experts were identified, and also selected with discriminant analysis. A number of provisional criteria sets that best represented the consensus of the experts were defined. Using other datasets, these clinically derived criteria sets as well as the statistically derived ASAS-IC were then tested for discriminative properties and for agreement with the end of trial efficacy by patient and doctor. Results: Forty experts completed the three Delphi rounds. The experts considered twice as many patients to be responders than the ASAS-IC (42 v 21). Overall agreement between experts and ASAS-IC was 62%. Spinal pain was considered the most important domain by most experts and was also selected as such by discriminant analysis. Provisional criteria sets with an agreement of ⩾80% compared with the consensus of the experts showed high placebo response rates (27–42%), in contrast with the ASAS-IC with a predefined placebo response rate of 25%. All criteria sets and the ASAS-IC discriminated well between active and placebo treatment (χ2=36–45; p<0.001). Compared with the end of trial efficacy assessment, the provisional criteria sets showed an agreement of 71–82%, sensitivity of 67–83%, and specificity of 81–88%. The ASAS-IC showed an agreement of 70%, sensitivity of 62%, and specificity of 89%. Conclusion: The ASAS-IC are strict in defining response, are highly specific, and consequently show lower sensitivity than the clinically derived criteria sets. However, those patients who are considered as responders by applying the ASAS-IC are acknowledged as such by the expert panel as well as by patients’ and doctors’ judgments, and are therefore likely to be true responders.

Impact of Certolizumab Pegol on Patient-Reported Outcomes in Patients With Axial Spondyloarthritis

Patient‐reported outcomes (PROs) provide an opportunity to collect important information relating to patient well‐being, which is often difficult for physicians to measure (e.g., quality of life, pain, fatigue, and sleep). Here we evaluate the effects of certolizumab pegol (CZP) on PROs during the 24‐week, double‐blind phase of the RAPID axial spondyloarthritis (SpA) trial, a phase 3 trial of axial SpA patients, including both ankylosing spondylitis (AS) and nonradiographic axial SpA patients.

A brief history of spa therapy [3] (multiple letters)

We read with great interest the article by Gudbjornsson and colleagues and concur with the accompanying leader by Dr Paget on the issue of corticosteroid associated osteoporosis. 2 Osteoporosis is a major public health problem, associated with significant morbidity and mortality, and is estimated to cost £614 million annually in England and Wales alone. Despite well published guidelines on the prevention and treatment of corticosteroid associated osteoporosis, as a profession, we are failing to meet the targets set by these guidelines. 4 In the light of the American College of Rheumatology guidelines in 2001, we performed an audit of our current practice relating to the issue of steroid prescription, calcium supplementation, measurement of bone density, and the prescription of antiresorptive treatment to see if we had been adhering to the recommendations of the National Osteoporosis Society. Our rheumatology department has a continually updated database on all current and past patients who have attended our unit. This contains information on patient demographics, primary rheumatological diagnosis, comorbid conditions, current drug treatment, past disease modifying treatment (including corticosteroids), and records all patient generated events, including outpatient and inpatient episodes. From our database of over 10 000 patients, we identified 258 patients who were currently receiving prednisolone and had been taking the drug for a minimum of three months. Forty patients were selected at random and case records were then reviewed. We recorded information on patient demographics, current prednisolone dose, the maximum prednisolone dose, and the reason for the prescription of corticosteroids. We looked at other identifiable risk factors for osteoporosis, the co-prescription of calcium supplements and treatment for osteoporosis and whether the patients had ever had a bone density measurement. Finally, we telephoned a selection of the patients to inquire if they had ever received verbal or written information on osteoporosis. Forty patients (29 female) were randomly selected. The median patient age was 63 years (range 33–85). The patients were taking a mean daily dose of 6.7 mg prednisolone (range 1–45) and had been prescribed prednisolone for a median of 6 years (range 3 months–20 years). The most common reason for the prescription of prednisolone was for polymyalgia rheumatica for 14 (35%) of those selected, followed by systemic lupus erythematosus (SLE) in nine (23%), rheumatoid arthritis or associated complications for four (10%), and mixed connective tissue disease for three (8%). There were also isolated prescriptions for juvenile idiopathic arthritis, dermatomyositis, polymyositis, psoriatic arthritis, Wegener’s granulomatosis, iritis, and unspecified systemic vasculitis. Encouragingly, 34 (85%) of our cohort were receiving some form of bone protective treatment: 22 (55%) were taking an oral bisphosphonate and one patient received intravenous pamidronate. Four of the postmenopausal women were taking hormone replacement therapy and two patients were receiving calcitriol. Twenty (50%) were prescribed calcium and vitamin D supplements, and this was the only treatment in eight (20%) of the cohort. However, of the six patients not receiving any form of bone therapy, five were over the age of 65 years and the one patient under the age of 65 years has been treated with prednisolone continuously for 20 years for SLE, up to a maximum dose of 80 mg/day. Twenty four (60%) of the 40 patients had bone density measured by dual x ray absorptiometry (DXA) scan. Of these, seven (29%) were normal, eight (33%) showed osteopenia, and nine (38%) demonstrated osteoporosis at the lumbar spine or the neck of the femur, or both. All patients who had either osteopenia or osteoporosis on DXA scan were treated with bone protective agents. We interviewed 24 patients by telephone. Eighteen (75%) recalled being informed of steroid side effects. Seven had received written information on steroids, but only three had received written information on osteoporosis. Although our results are encouraging, a significant number of patients are not being treated to prevent osteoporosis and reduce future fracture risk. The fact that all patients with an abnormal bone density scan are treated is reassuring, but we cannot be sure what proportion of patients who have not been scanned require treatment. In 1996, Walsh and colleagues found that only 14% of patients receiving long term prednisolone were receiving some form of preventive treatment against osteoporosis. Although matters have improved to a degree, a substantial proportion of patients treated with steroids is still undertreated and considerable progress has to be made nationally and internationally to prevent further bone associated morbidity among patients treated with corticosteroids.

Dissemination and evaluation of the European League Against Rheumatism recommendations for the role of the nurse in the management of chronic inflammatory arthritis: Results of a multinational survey among nurses, rheumatologists and patients

OBJECTIVES The aims of this study were to disseminate, assess agreement with, assess the application of and identify potential barriers for implementation of the European League Against Rheumatism (EULAR) recommendations for the role of nurses in the management of chronic inflammatory arthritis (CIA) using a survey of nurses, rheumatologists and patients. METHODS A Web-based survey was distributed across Europe and the USA using snowball sampling. Levels of agreement and application were assessed using a 0-10 rating scale (0 = none, 10 = full agreement/application). Reasons for disagreement and potential barriers to application of each recommendation were sought. Regional differences with respect to agreement and application were explored. RESULTS In total, 967 nurses, 548 rheumatologists and 2034 patients from 23 countries participated in the survey. Median level of agreement was high in all three groups, ranging from 8 to 10 per recommendation. Median level of application was substantially lower, ranging from 0 to 8 per recommendation. Agreement and application were lowest in Eastern and Central Europe. The most commonly reported reasons for incomplete agreement were too many other responsibilities (nurses), doubts about knowledge of the nurse (rheumatologists) and fear of losing contact with the rheumatologist (patients). The most commonly reported barriers to the application were time constraints and unavailability of service. Rheumatologists responses suggested that nurses had insufficient knowledge to provide the recommended care. CONCLUSION The EULAR recommendations for the role of nurses in the management of CIA have been disseminated among nurses, rheumatologists and patients across Europe and the USA. Agreement with these recommendations is high, but application is lower and differed across regions.

General Practitioners' Perceptions of Their Ability to Identify and Refer Patients with Suspected Axial Spondyloarthritis: a Qualitative Study

Objective. To explore the knowledge, beliefs, and experiences of general practitioners (GP) about inflammatory back pain (IBP) and axial spondyloarthritis (axSpA) and potential barriers for referral of patients suspected of having axSpA. Methods. A qualitative study involving semistructured interviews with GP was conducted. Transcripts of the interviews were independently read and annotated by 2 readers. Illustrative themes were identified and a coding system to categorize the data was developed. Results. Ten GP (all men; mean age 49 yrs) were interviewed. All could adequately describe “classic” ankylosing spondylitis (AS) and mentioned chronic back pain and/or stiffness as key features. All GP thought that AS is almost exclusively diagnosed in men. Six GP knew that there is a difference between mechanical back pain and IBP, but could recall only a limited number of variables indicative of IBP, such as awakening night pain (4 GP), insidious onset of back pain (1 GP), improvement with movement (1 GP), and (morning) stiffness (2 GP). Two GP mentioned peripheral arthritis as other SpA features, none mentioned dactylitis or enthesitis. GP awareness of associated extraarticular manifestations was low. Most GP expressed that (practical) referral measures would be useful. Conclusion. GP are aware of “classic”, but longterm features of axSpA. Knowledge about the disease spectrum and early detection is, however, limited. Addressing these issues in training programs may improve recognition of axSpA in primary care. This may ultimately contribute to earlier referral, diagnosis, and initiation of effective treatment in patients with axSpA.

OP0182 Prevention of Rheumatoid Arthritis by B Cell Directed Therapy in The Earliest Phase of The Disease: The Prairi Study

Background Systemic autoimmunity may precede the development of clinical signs and symptoms of seropositive rheumatoid arthritis (RA), which offers a window of opportunity to delay or prevent clinically manifest arthritis by targeted intervention. This could represent a paradigm shift from treatment to prevention1. Objectives To explore if a single infusion of rituximab (anti-CD20 antibody) can prevent or delay the onset of clinically manifest arthritis in individuals at risk of developing autoantibody positive RA. Methods Eighty-two subjects with arthralgia who had never had clinically manifest arthritis and never used disease-modifying antirheumatic drugs were included in a multicentre, randomised, double-blind, placebo-controlled clinical trial. They were positive for both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor and they had CRP levels ≥3 mg/l and/or subclinical synovitis on ultrasound or MRI of the hands. Subjects were randomized to receive a single iv infusion of either 1000 mg rituximab or placebo after 100 mg methylprednisolone premedication in each group. Subjects were prospectively followed to assess development of clinically manifest arthritis. We performed Kaplan-Meier survival analysis, Cox regression analysis and determined Treatment*Time Cox proportional hazards. Results Eighty-one individuals (52 females; mean age 53 (IQR 13.5) years) received treatment, which was generally well tolerated. One patient withdrew before treatment. The median follow up was 27.0 months (IQR 25.0), during which 30 subjects developed arthritis: 16/40 (40%) in the placebo group and 14/41 (34%) in the rituximab group, after a median period of 11.5 (interquartile range [IQR] 12.5) months in the placebo group versus 16.5 (IQR 19.0) months in the rituximab group. Whereas the risk for development of arthritis in the placebo group was 40%, we found a reduction of 53% of this risk in the rituximab group at 18 months follow up (HR (95%CI)=0.475 (0.190–1.191)). At the 25% quartile (75% free of arthritis) of the cumulative arthritis-free survival, there was a delay in the development of arthritis of 12.0 months (12 months in the placebo group versus 24 months in the rituximab group. As expected, this effect attenuated over time. Treatment*Time Cox proportional hazard analysis showed that the beneficial effect of rituximab was statistically significant (P<0.0001) Conclusions A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA. This is the first study evaluating the effects of a biopharmaceutical in this population, and the results strongly support the rationale for future clinical trials aimed at prevention of RA by a targeted intervention. References Gerlag DM, Norris JM, Tak PP. RA: from risk factors and pathogenesis to prevention: Towards prevention of autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment. Rheumatology (Oxford). 2015 Sep 15. Review Acknowledgement N de Vries, DJ van Schaardenburg, E Brouwer, T Huizinga Disclosure of Interest D. Gerlag Shareholder of: GlaxoSmithKline, Grant/research support from: Dutch Arthritis Foundation, Netherlands Organisation for Health Research and Development, Employee of: GlaxoSmithKline, M. Safy: None declared, K. Maijer: None declared, M. de Hair: None declared, S. Tas: None declared, M. Starmans-Kool: None declared, A. van Tubergen: None declared, M. Janssen: None declared, P.-P. Tak Shareholder of: GlaxoSmithKline, Grant/research support from: Dutch Arthritis Foundation, Netherlands Organisation for Health Research and Development, Employee of: GlaxoSmithKline