Matthias Englbrecht

Elaboration of the preliminary Rheumatoid Arthritis Impact of Disease (RAID) score: a EULAR initiative

Background: Current response criteria in rheumatoid arthritis (RA) usually assess only three patient-reported outcomes (PROs): pain, functional disability and patient global assessment. Other important PROs such as fatigue are not included. Objective: To elaborate a patient-derived composite response index for use in clinical trials in RA, the RA Impact of Disease (RAID) score. Methods: Ten patients identified 17 domains or areas of health relevant for inclusion in the score, then 96 patients (10 per country in 10 European countries) ranked these domains in order of decreasing importance. The seven most important domains were selected. Instruments were chosen for each domain after extensive literature research of psychometric properties and expert opinion. The relative weight of each of the domains was obtained from 505 patients who were asked to “distribute 100 points” among the seven domains. The average ranks of importance of these domains were then computed. Results: The RAID score includes seven domains with the following relative weights: pain (21%), functional disability (16%), fatigue (15%), emotional well-being (12%), sleep (12%), coping (12%) and physical well-being (12%). Weights were similar across countries and across patient and disease characteristics. Proposed instruments include the Health Assessment Questionnaire and numerical ratings scales. Conclusion: The preliminary RAID score is a patient-derived weighted score to assess the impact of RA. An ongoing study will allow the final choice of questionnaires and assessment of validity. This score can be used in clinical trials as a new composite index that captures information relevant to patients.

Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative

Objective A patient-derived composite measure of the impact of rheumatoid arthritis (RA), the rheumatoid arthritis impact of disease (RAID) score, takes into account pain, functional capacity, fatigue, physical and emotional wellbeing, quality of sleep and coping. The objectives were to finalise the RAID and examine its psychometric properties. Methods An international multicentre cross-sectional and longitudinal study of consecutive RA patients from 12 European countries was conducted to examine the psychometric properties of the different combinations of instruments that might be included within the RAID combinations scale (numeric rating scales (NRS) or various questionnaires). Construct validity was assessed cross-sectionally by Spearman correlation, reliability by intraclass correlation coefficient (ICC) in 50 stable patients, and sensitivity to change by standardised response means (SRM) in 88 patients whose treatment was intensified. Results 570 patients (79% women, mean±SD age 56±13 years, disease duration 12.5±10.3 years, disease activity score (DAS28) 4.1±1.6) participated in the validation study. NRS questions performed as well as longer combinations of questionnaires: the final RAID score is composed of seven NRS questions. The final RAID correlated strongly with patient global (R=0.76) and significantly also with other outcomes (DAS28 R=0.69, short form 36 physical −0.59 and mental −0.55, p<0.0001 for all). Reliability was high (ICC 0.90; 95% CI 0.84 to 0.94) and sensitivity to change was good (SRM 0.98 (0.96 to 1.00) compared with DAS28 SRM 1.06 (1.01 to 1.11)). Conclusion The RAID score is a patient-derived composite score assessing the seven most important domains of impact of RA. This score is now validated; sensitivity to change should be further examined in larger studies.

Periarticular Bone Structure in Rheumatoid Arthritis Patients and Healthy Individuals Assessed by High-Resolution Computed Tomography

OBJECTIVE To define the nature of structural bone changes in patients with rheumatoid arthritis (RA) compared with those in healthy individuals by using the novel technique of high-resolution microfocal computed tomography (micro-CT). METHODS Fifty-eight RA patients and 30 healthy individuals underwent a micro-CT scan of the proximal wrist and metacarpophalangeal joints. Bone lesions such as cortical breaks, osteophytes, and surface changes were quantified on 2-dimensional (2-D) slices as well as by using 3-D reconstruction images, and exact localization of lesions was recorded. RESULTS Micro-CT scans could detect bone lesions <0.5 mm in width or depth. Small erosions could be observed in healthy individuals and RA patients, whereas lesions >1.9 mm in diameter were highly specific for RA. Cortical breaks were mostly found along the radial sites of the metacarpal heads. No significant difference in the presence of osteophytes between healthy individuals and RA patients was found. Cortical surface changes, presumably cortical thinning and fenestration, became evident from 3-D reconstructions and were more pronounced in RA patients. CONCLUSION Micro-CT allows exact detection of morphologic changes of juxtaarticular bone in healthy individuals and RA patients. Even healthy individuals occasionally show bone changes, but the severity of these lesions, with the exception of osteophytes, is greater in RA patients. Thus, micro-CT allows accurate differentiation among physiologic bone changes in joints and among types of pathologic bone damage resulting from RA.

A comparative study of periarticular bone lesions in rheumatoid arthritis and psoriatic arthritis

Background Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are both destructive arthritides but may differ substantially in their periarticular bone changes. Objectives To investigate the differences in the structural changes of periarticular bone in patients with PsA and RA by a high-resolution imaging technique designed to visualise the bone architecture. Methods 30 patients with PsA and 58 patients with RA received a µCT scan to compare structural bone changes in the metacarpophalangeal joints of the dominantly affected hand. Number, extent, form and distribution of bone erosions, osteophytes and cortical thinning were recorded. In addition, the size and depth of bone erosions and the size of osteophytes were determined. Results Patients with PsA and RA had the same number of bone erosions, but they were less severe and overall smaller in size and depth in PsA. Erosions in PsA were mostly Ω-shaped and tubule-shaped, whereas U-shaped lesions were most typical for RA. Erosions in PsA were more evenly distributed, lacking the strong preponderance for the radial sites found in RA. Osteophytes were increased in number, extent and size in PsA as compared with RA, often affecting the entire circumference of bone (‘bony corona’). Conclusions High-resolution µCT imaging shows profound differences in periarticular bone changes between PsA and RA. Smaller Ω-shaped and tubule-shaped bone erosions as well as large sometimes corona-shaped osteophytes are typical for PsA. These data suggest that mechanisms of bone repair may be more active in PsA than in RA.

Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion

Objectives To investigate whether bone erosions in patients with rheumatoid arthritis (RA) show evidence of repair. Methods 127 erosions were identified in metacarpophalangeal joints 2–4 of the right hands of 30 RA patients treated with tumour necrosis factor inhibitors (TNFi) and 21 sex, age and disease activity-matched patients treated with methotrexate. All erosions were assessed for their exact maximal width and depth by high-resolution µCT imaging at baseline and after 1 year. Results All erosions detected at baseline could be visualised at follow-up after 1 year. At baseline, the mean width of bone erosions in the TNFi group was 2.0 mm; their mean depth was 2.3 mm, which was not significantly different from the methotrexate-treated group (width 2.4 mm; depth 2.4 mm). Mean depth of erosions significantly decreased after 1 year of treatment with TNFi (−0.1 mm; p=0.016), whereas their width remained unchanged. In contrast, mean depth and width of erosive lesions increased in the methotrexate-treated group. The reduction in the depth of lesions was confined to erosions showing evidence of sclerosis at the base of the lesion. Moreover, deeper lesions in the TNFi group were particularly prone to repair (−0.4 mm; p=0.02) compared with more shallow lesions. Conclusions Bone erosions in RA patients treated with TNFi show evidence of limited repair in contrast to bone erosions in patients treated with methotrexate. Repair is associated with a decrease in the depth of lesions and sclerosis at the bases of the lesions. Repair thus emerges from the endosteal rather than periosteal bone compartment and probably involves the bone marrow.

A detailed comparative study of high‐resolution ultrasound and micro–computed tomography for detection of arthritic bone erosions

OBJECTIVE To test whether bony lesions appearing on ultrasound (US) imaging are cortical breaks detectable by micro-computed tomography (micro-CT). METHODS Twenty-six subjects (14 with rheumatoid arthritis, 6 with psoriatic arthritis, and 6 healthy controls) were assessed for bone erosions at the radial, palmar, and dorsal regions of the second metacarpophalangeal (MCP) joint and the palmar and dorsal regions of the third and fourth MCP joints. All patients underwent US and, for validation of the results, micro-CT scanning. The prevalence and severity of bone erosions as determined by US and by micro-CT were recorded and compared. RESULTS Overall there was a good correlation between the severity of erosions as assessed by US and by micro-CT (r = 0.463, P < 0.0001). False-negative results (US negative/micro-CT positive) were obtained in only 9.9% of the joint regions and were mostly due to small erosive lesions at the dorsal sides of the MCP joints. False-positive results (US positive/micro-CT negative) were more frequent (28.6%) and were primarily based on vascular bone channels at the palmar sides of the MCP joints as well pseudo-erosions created by osteophytes. CONCLUSION These data show that the majority of bone lesions appearing on US are indeed bone erosions with a cortical break. The sensitivity of US for detecting bone erosions was high and there was a good correlation between the severity of bone erosions as assessed by US and as assessed by micro-CT. Specificity of US for bone erosions was substantially lower, suggesting that smaller lesions seen on US do not always represent breaks in the cortical bone surface.

Churg-Strauss Syndrome in Childhood: A Systematic Literature Review and Clinical Comparison with Adult Patients

OBJECTIVE To describe the clinical characteristics of children with Churg-Strauss syndrome (CSS) in comparison with adult patients. MATERIALS AND METHODS A systematic literature analysis was performed in the Medline database up to November 2007 and in rheumatology and pulmonology meeting scientific abstracts 2003-2007. Articles with reported childhood CSS cases were retrieved; clinical data were recorded. Descriptive statistical analyses and a comparison with 2 published adult CSS cohorts were performed. RESULTS Thirty-three cases of childhood CSS were identified. The mean age was 12 years and the male-to-female ratio was 0.74. All patients had significant eosinophilia and asthma. Histological evidence of eosinophilia and/or vasculitis was present in virtually all patients. Antineutrophil cytoplasmic antibodies were found in 25% of children with CSS. Initial treatment was corticosteroid monotherapy in 76% of childhood CSS patients, while 24% received additional immunosuppressive therapy. Another 18% required further immunosuppression at follow-up due to frequent relapses. Six deaths (18%), all related to the underlying disease, occurred after a mean disease duration of 14 months. As compared with adult CSS patients, children had a predominance of cardiopulmonary disease manifestations, a lower rate of peripheral nerve involvement, and higher mortality. CONCLUSIONS Many aspects of CSS are similar in childhood and adult patients. However, pulmonary and cardiac involvement is predominant in pediatric CSS and mortality is substantial.

Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA

Objective To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) Methods 242 patients with RA received high-resolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula. Results Of the 238 patients, 112 patients showed RF and ACPAs (ACPAs+RF+), 28 only RF (RF+), 29 only ACPAs (ACPA+) and 69 were antibody negative (NEG). Erosion number and size were highest in RF+ACPAs+ patient group with significant differences compared with NEG patients with respect to erosion number (p=0.001) and to ACPA-negative patients with respect to erosion size (p<0.001). Results maintained significance in a linear mixed model showing ACPAs+RF+ status and disease duration being associated with higher number (p=0.017 and p=0.005, respectively), and larger size (p=0.014 and p=0.013, respectively) of bone erosions. Furthermore, erosion size was influenced by the presence and titre of RF only in ACPA-positive patients with RA but not in ACPA-negative patients. Conclusions ACPAs and RF show an additive effect on erosion number and erosion size. Concomitant presence of ACPAs and RF is associated with higher erosive disease burden in patients with RA. Furthermore, RF influences erosion size only in ACPA-positive but not in ACPA-negative patients.

Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: a micro CT study

Introduction Interleukin-6 receptor (IL-6R) blockade improves the signs and symptoms of rheumatoid arthritis (RA) and retards bone damage. Whether IL-6R blockade allows repair of existing bone erosions is so far unclear. Methods This study examined bone erosions in the metacarpophalangeal joints of 20 patients receiving treatment with the IL-6R blocker tocilizumab using micro CT (µCT). The maximal width and depth of individual bone erosions was measured at baseline and after 1 year of treatment. Results 133 bone erosions were identified at baseline with a mean (±SD) size of 2.23±1.26 mm and depth of 2.16±1.50 mm. Distribution analysis showed predominant involvement of the second compared with the third and fourth metacarpophalangeal joints, the metacarpal heads compared with the phalangeal bases and the radial quadrants compared with all other surfaces. Repair of bone erosions during tocilizumab treatment was confined to those lesions showing sclerosis at baseline and/or at follow-up and those with a width larger than 1.6 mm. The mean decrease in width of sclerosed erosions was thus 0.14±0.05 mm (p=0.0086) and 0.20±0.08 mm (p=0.019) for sclerosing lesions after 1 year of treatment. Conclusions Blockade of IL-6R by tocilizumab can induce limited repair in a subset of erosions, particularly in large lesions with sclerosis. Repair of erosions during tocilizumab treatment reflects the favourable impact of IL-6R blockade on local bone remodelling in patients with RA.

Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative

Objective. To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA). Methods. A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008–09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice. Results. A total of 49 242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice. Conclusions. Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.