K. de Vlam

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal

Objective: Non-radiographic axial spondyloarthritis (SpA) is characterised by a lack of definitive radiographic sacroiliitis and is considered an early stage of ankylosing spondylitis. The objective of this study was to develop candidate classification criteria for axial SpA that include patients with but also without radiographic sacroiliitis. Methods: Seventy-one patients with possible axial SpA, most of whom were lacking definite radiographic sacroiliitis, were reviewed as “paper patients” by 20 experts from the Assessment of SpondyloArthritis international Society (ASAS). Unequivocally classifiable patients were identified based on the aggregate expert opinion in conjunction with the expert-reported level of certainty of their judgement. Draft criteria for axial SpA were formulated and tested using classifiable patients. Results: Active sacroiliitis on magnetic resonance imaging (MRI) (odds ratio 45, 95% CI 5.3 to 383; p<0.001) was strongly associated with the classification of axial SpA. The knowledge of MRI findings led to a change in the classification of 21.1% of patients. According to the first set of candidate criteria (sensitivity 97.1%; specificity 94.7%) a patient with chronic back pain is classified as axial SpA in the presence of sacroiliitis by MRI or x rays in conjunction with one SpA feature or, if sacroilitiis is absent, in the presence of at least three SpA features. In a second set of candidate criteria, inflammatory back pain is obligatory in the clinical arm (sensitivity 86.1%; specificity 94.7%). Conclusion: The ASAS group has developed candidate criteria for the classification of axial SpA that include patients without radiographic sacroiliitis. The candidate criteria need to be validated in an independent international study.

European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies

Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

Treatment recommendations for psoriatic arthritis

Objective: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. Methods: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. Results: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. Conclusions: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update

Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial

Objective: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. Methods: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. Results: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin’s lymphoma (infliximab). Conclusion: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

Direct costs of ankylosing spondylitis and its determinants: an analysis among three European countries

Objective: To assess direct costs associated with ankylosing spondylitis (AS). To determine which variables, including country, predict costs. Methods: 216 patients with AS from the Netherlands, France, and Belgium participated in a two year observational study and filled in bimonthly economic questionnaires. Disease related healthcare resource use was measured and direct costs were calculated from a societal perspective (true cost estimates) and from a financial perspective (country-specific tariffs). Predictors of costs were assessed using Cox’s regression analysis. Results: 209 patients provided sufficient data for cost analysis. Mean annual societal direct costs for each patient were €2640, of which 82% were direct healthcare costs. In univariate analysis costs were higher in the Netherlands than in Belgium, but this difference disappeared after adjusting for baseline differences in patients’ characteristics among countries. Longer disease duration, lower education, worse physical function, and higher disease activity were predictors of costs. Mean annual direct costs from a financial perspective were €2122, €1402, and €941 per patient in the Netherlands, France, and Belgium, respectively. For each country, costs from a financial perspective were significantly lower than costs from a societal perspective. Conclusion: Direct costs for AS are substantial in three European countries but not significantly different after adjusting for baseline characteristics among countries. Worse physical function and higher disease activity are important determinants of costs, suggesting better disease control might reduce the costs of AS. The difference in costs from a societal and financial perspective emphasises the importance of an economic analysis.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography

Objective To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). Methods CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. Results In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. Conclusions Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence ‘inflammation–FD–new bone formation’ was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

Costs of ankylosing spondylitis in three European countries: the patient’s perspective

Objective: To assess a patient’s out of pocket costs, income loss, time consumption, and quality of life (QoL) due to ankylosing spondylitis (AS) in three European countries and to assess variables predicting these outcomes. Methods: 216 patients with AS from the Netherlands, France, and Belgium participated in a two year study. Health resource use, days absent from work, time lost, and quality of life (EuroQol) were assessed by bimonthly questionnaires. AS related healthcare and non-healthcare expenditure and income loss were calculated taking into account country-specific regulations. Predictors of costs, time consumption, and QoL were analysed by Cox’s regression. Results: 209 patients provided data for cost analysis. Average annual healthcare and non-healthcare expenditure was €431 per patient and average annual income loss was €1371 per patient. Healthcare costs were highest for Belgian and lowest for French patients, while non-healthcare costs were highest for Dutch patients. A patient’s total costs were associated with higher age and worse physical function. On average, patients with AS needed 75 minutes additional time a day because of AS. Worse physical function and higher disease activity predicted time consumption. After adjusting for baseline confounders, QoL was worse in Belgian and French than in Dutch patients. Peripheral arthritis, worse physical function, higher disease activity, and loss of income contributed to worse QoL. Conclusion: AS is time consuming and associated with substantial out of pocket costs. Belgian patients incur the highest healthcare payments. Poor physical function increases patient’s costs and time consumption. Loss of income is associated with lower QoL.

Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis : results of a study among 1507 rheumatologists

Background: Ten ASAS/EULAR recommendations for the management of ankylosing spondylitis (AS) were published in 2006. Objectives: (a) To disseminate and (b) to evaluate conceptual agreement with, and (c) application of, these recommendations as well as (d) potential barriers to the application. Methods: A questionnaire was sent to rheumatologists in 10 countries. It included (a) the text of the recommendations; (b) rheumatologists’ demographic variables; (c) two numerical rating scales from 1 to 10 for each recommendation: conceptual agreement with, and application of, the recommendation (10 indicates maximal agreement and maximal application); and (d) a list of potential barriers to the application of the recommendation. Statistical analysis included descriptive and multivariate analyses. Results: 7206 questionnaires were sent out; 1507 (21%) were returned. Of the 1507 answering rheumatologists, 62% were men, mean (SD) age 49 (9) years, and 34% had an academic position. Conceptual agreement with the recommendations was high (mean (SD) for all recommendations 8.9 (0.9)). Self-reported application was also high (8.2 (1.0)). The difference between agreement and application varied across recommendations and countries. The most pronounced discrepancies were reported for use of anti-tumour necrosis factor drugs in a few countries, with funding as the most commonly reported barrier for application of this recommendation. Conclusion: This large project has helped the dissemination of the ASAS/EULAR recommendations for the management of AS and shows that conceptual agreement with the recommendations is very high. The project also highlights inequalities in access to healthcare for European citizens with AS.

Differential association of polymorphisms in the TNFα region with psoriatic arthritis but not psoriasis

Objective: To investigate the potential association of tumour necrosis factor α (TNFα) microsatellite and promoter alleles with psoriatic arthritis (PsA). Methods: DNA from 89 white patients with PsA, 65 patients with psoriasis, and 99 healthy white controls was investigated for two TNFα promoter (–238 and –308) and three microsatellite polymorphisms (TNFa, c, and d). Patients had previously been studied by serology for HLA class I antigens and by sequence-specific polymerase chain reaction for DRB1* alleles. In addition, TNFα production of Ficoll separated peripheral blood mononuclear cells (PBMC) into culture supernatants after stimulation with lipopolysaccharide, αCD3 antibodies, phytohaemagglutinin, and streptococcal superantigen C was determined. Results: A significant, HLA class I independent increase of the TNFa6c1d3 haplotype was found in the group with PsA but not among patients with psoriasis (32% v 8%, pc<0.008; relative risk (RR)=5.3). In addition, patients with PsA showed a marked decrease of the TNF308A promoter allele (6% v 18%; pc<0.008; RR=3.5) compared with healthy controls, which was independent of the increased frequency of the –238A polymorphism in this group. PBMC from patients with PsA secreted significantly less TNFα than cells from patients without arthritis. In particular, the TNFa6 microsatellite was associated with decreased TNFα production. Conclusion: These data indicate that allelic variations at the TNFα locus influence susceptibility to PsA. Decreased production of TNFα is at least in part genetically determined and might be related to the development of arthritis. However, the association of the TNF308G allele with the disease also points to other disease related haplotypes with still unknown susceptibility genes.