M. Ward

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs

Objectives To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. Methods The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. Results Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence >5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1–5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. Conclusions Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies

Objectives To develop recommendations for monitoring patients with systemic lupus erythematosus (SLE) in clinical practice and observational studies and to develop a standardised core set of variables to monitor SLE. Methods We followed the European League Against Rheumatism (EULAR) standardised procedures for guideline development. The following techniques were applied: nominal groups, Delphi surveys for prioritisation, small group discussion, systematic literature review and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine. Results A total of 10 recommendations have been developed, covering the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment. A ‘core set’ of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specific organ assessments that were viewed as part of good clinical practice were discussed and included in the flow chart. Conclusions A set of recommendations for monitoring patients with SLE in routine clinical practice has been developed. The use of a standardised core set to monitor patients with SLE should facilitate clinical practice, as well as the quality control of care for patients with SLE, and the collection and comparison of data in observational studies.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVEnTo make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).nnnMETHODSnThe project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007).nnnRESULTSnEleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue.nnnCONCLUSIONnThese recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Treatment-related improvement in physical function varies with duration of rheumatoid arthritis. A pooled analysis of clinical trial results.

Background: Physical function in rheumatoid arthritis (RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs). Methods: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as “biologics”, or “traditional” disease modifying antirheumatic drugs (DMARDs), and “placebo”. We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models. Results: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (pu200a=u200a0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration. Conclusion: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo.

Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis

Objective To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). Method We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon–intron boundaries, and 5u2005kb flanking DNA in the 5′ and 3′ UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into ‘mild’ and ‘severe’ groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. Results Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10−5), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10−3). There was no observed association between radiographic severity and HLA-B*27. Conclusions These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

Methods of deriving EULAR/ACR recommendations on reporting disease activity in clinical trials of patients with rheumatoid arthritis

Objective: To use an evidence-based and consensus-based approach to elaborate recommendations on how to report disease activity in clinical trials of patients with rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods: After an initial expert meeting, during which relevant research questions were identified, a systematic literature search was performed using Medline, Embase and the Cochrane Library as sources. To ensure literature retrieved was comprehensive, we emphasised search algorithms that were sensitive rather than specific. The results of the literature search were discussed by the expert panel, modified and expanded, and were used as the basis for the elaboration of the recommendation in the consensus process. Finally, an independent ACR panel approved these items with some minor modifications. Results: The following pieces of evidence were obtained from the literature search: (1) timing and the sustaining of a response is relevant to achieve better outcomes; (2) composite disease activity indices have been used to define low disease activity and remission and these definitions have been validated as has the American Rheumatism Association (ARA) remission criteria. The “patient-reported symptom state” (PASS) is not yet well validated; (3) evidence was obtained to identify those measures, scales and patient-reported instruments, for which there is a documented association with relevant outcomes; (4) baseline disease activity is associated with disease activity levels at the end of follow-up; and (5) there was not sufficient evidence relating the added benefit of MRI or ultrasound over clinical assessments. Most data stemmed from observational studies rather than clinical trials and literature review was supplemented by input from experts. The results served as the basis for the elaboration of the seven recommendations by the experts. Conclusions: The approach based on scientific evidence from the literature as well as on expert input provided sufficient information to derive recommendations on reporting disease activity in RA clinical trials. The methodology, results and conclusions of this project were endorsed by EULAR and the ACR.

OP0092 Remission in Sle: Consensus Findings from a Large International Panel on Definitions of Remission in SLE (DORIS)

Background Treat-to-target recommendations identified “remission” as a target in SLE but recognize that there is no generally accepted definition for remission in this disease. Objectives To achieve consensus, in a large multi-party international panel, on potential definitions for remission in SLE. Methods An international expert panel of sixty rheumatologists, nephrologists, dermatologists, clinical immunologists, and patient representatives participated in preparatory exercises, a full-day face-to-face meeting, and follow-up exercises and electronic voting rounds. Results Eight key statements regarding remission in SLE achieved >90% agreement (table). There were different viewpoints on the required duration of remission. In addition, the panel expressed strong support (>90%) for the following principles which will guide the further development of remission definitions: I. A definition of remission in SLE will be worded as follows: Remission in SLE is a durable state characterized by [a definition of: absence of symptoms, signs, abnormal labs, (serology)] Ia. Remission-off-therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials. Ib. Remission-on-therapy allows patients to be treated with maintenance antimalarials, stable, low-dose steroids (prednisone ≤5 mg/d), maintenance immunosuppressives and/or stable (maintenance) biologics. II. Assessment of clinical symptoms and signs should be based on a validated index, e.g., clinical-SLEDAI =0, BILAG D/E only, clinical ECLAM =0; supplemented with PhysGA <0.5 (0-3), and with labs included. III. For testing the construct validity of each potential remission definition the most appropriate outcomes (dependent variables) are: Death, Damage, Flares, and HR-QOL measures. Conclusions The work of this international consensus panel provides a framework for testing individual definitions of remission against longer-term outcomes. Disclosure of Interest R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, C. Aranow: None declared, G. Bertsias: None declared, E. Bonfá: None declared, R. Cervera: None declared, N. Costedoat-Chalumeau: None declared, T. Dörner: None declared, F. Houssiau: None declared, K. Lerstrom: None declared, E. Morand: None declared, M. Mosca: None declared, S. Navarra: None declared, M. Petri: None declared, M. Urowitz: None declared, A. Voskuijl: None declared, A. Voss: None declared, M. Ward: None declared, V. Werth: None declared, M. Schneider: None declared

Standards of comparison and discordance in rheumatoid arthritis global assessments between patients and clinicians

Patient‐physician discordance in health status ratings may arise because patients use temporal comparisons (comparing their current status with their previous status), while clinicians use social comparisons (comparing this patients status to that of other patients, or to the full range of disease severity possible) to guide their assessments. We compared discordance between patients with rheumatoid arthritis (RA) and clinicians, using either the conventional patient global assessment (PGA) or a rating scale with 5 anchors describing different health states. We hypothesized that discordance would be smaller with the rating scale because clinicians likely used similar social comparisons when making global assessments.

Measures of arthritis activity associated with patient-reported improvement in rheumatoid arthritis when assessed prospectively versus retrospectively.

The patient global assessment (PGA) is intended to provide an integrated summary of all symptoms of arthritis, but it is not clear which disease features most impact patients assessments of changes in their overall status. We investigated what aspects of rheumatoid arthritis (RA) activity correlated best with prospectively measured changes in the PGA and with patients’ retrospective judgments of improvement.The patient global assessment (PGA) occupies a central place among measures of rheumatoid arthritis (RA). Not only is the PGA one of the core measures in the American College of Rheumatology (ACR) response criteria, but it is the only patient-reported measure included in composite RA activity measures and in new criteria for remission. The PGA is an attractive measure because it is intended to capture, in a single item, an overall summary of the impact of RA on a patients well-being. .However, its loosely-defined nature may contribute to wide variation among patients in the aspects of RA that are emphasized in marking the PGA, and which may be influenced by mood or other psychological factors. In several cross-sectional analyses, pain severity was the dominant influence on the PGA, accounting for up to 75% of inter-patient variation in ratings (1–7). Physical functioning, fatigue, depression, and in some studies, joint counts, were also important. The relative contribution of these features is difficult to assess because not all studies included measures of depression, fatigue, stiffness, or joint counts. A study that reported a major contribution of depression to the PGA did not include a measure of pain (8). n nTo understand which aspects of RA influence patients’ assessments of change in their status, it is important to perform longitudinal comparisons, rather than rely on indirect between-patient comparisons of cross-sectional studies. Few longitudinal studies have investigated which RA activity measures are associated with changes in the PGA (5, 9–11). One study examined only pain and physical functioning, another only the Disease Activity Score (DAS), and the single study that examined fatigue and depression did not include joint counts. n nIn clinical practice, informal appraisals of patients’ overall status are more common than formal measures such as the PGA. Universal questions to patients include how they feel now and if they feel better. These appraisals are retrospective judgments that, like the PGA, are intended to integrate diverse aspects of disease into a single assessment. However, because they depend on recall, changes reported retrospectively may differ from those measured prospectively on measures such as the PGA, and the validity of retrospective judgments of improvement has been questioned (12). n nOur first goal was to identify the RA-related measures associated with prospectively measured changes in the PGA. If changes in clinical factors other than pain were associated with changes in PGA, it would validate the PGA as a summary measure of multiple aspects of RA. We were also interested in whether depression and fatigue were independently associated with changes in the PGA. Our second goal was to identify if changes in RA activity measures were associated with patients’ retrospective judgments of improvement in overall arthritis status as a way to validate this outcome measure. Our third goal was to compare the RA activity measures that were associated with patients retrospective judgments with those associated with the PGA. The former directly reflects the assessments provided by patients in clinical practice, and the comparison would provide insight into how patients form their appraisals of improvement.