Fabian Stemmler

Age- and Sex-Dependent Changes of Intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis.

The objective of this cross‐sectional study was to define normal sex‐ and age‐dependent values of intra‐articular bone mass and microstructures in the metacarpal heads of healthy individuals by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra‐articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR‐pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra‐articular (intracapsular) bone margins. These data were applied in measuring intra‐articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra‐articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra‐articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm3) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra‐articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex‐ and age‐adjusted controls. Standard sex‐ and age‐dependent values for physiological intra‐articular bone were defined. Postmenopausal state and RA led to significant decrease of intra‐articular bone.

Early Changes of the Cortical Micro-Channel System in the Bare Area of the Joints of Patients With Rheumatoid Arthritis: CoMiC SYSTEM CHANGES IN EARLY RA

To characterize the specific structural properties of the erosion‐prone bare area of the human joint, and to search for early microstructural changes in this region during rheumatoid arthritis (RA).Objective: To characterize the specific structural properties of the erosion-prone bare area of the human joint and to search for early microstructural changes in this region during rheumatoid arthritis Methods: An initial cadaveric study was used for exact localization of the bare area of the metacarpal heads, detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral computed tomography (HR-pQCT) and, after anatomical dissection, their validation by micro-computed tomography (μCT). In the second part, number and distribution of CoMiCs were analyzed in 105 healthy individuals and 107 RA patients with similar sex and age distribution. Results: HR-pQCT investigation combined with adaptive thresholding allowed detection of CoMiCs in the bare area of cadaveric joints. Their existence in the bare area was additionally validated by μCT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20-49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint. Conclusion: CoMiCs represent a new form of structural change in the joints of patients with RA. While CoMiCs increase with age, RA patients develop such changes much earlier in life and already at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA. This article is protected by copyright. All rights reserved.

Rheumatoid arthritis is characterized by early changes of the cortical micro-channel (CoMiC) system in the bare area of the joints

To characterize the specific structural properties of the erosion‐prone bare area of the human joint, and to search for early microstructural changes in this region during rheumatoid arthritis (RA).Objective: To characterize the specific structural properties of the erosion-prone bare area of the human joint and to search for early microstructural changes in this region during rheumatoid arthritis Methods: An initial cadaveric study was used for exact localization of the bare area of the metacarpal heads, detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral computed tomography (HR-pQCT) and, after anatomical dissection, their validation by micro-computed tomography (μCT). In the second part, number and distribution of CoMiCs were analyzed in 105 healthy individuals and 107 RA patients with similar sex and age distribution. Results: HR-pQCT investigation combined with adaptive thresholding allowed detection of CoMiCs in the bare area of cadaveric joints. Their existence in the bare area was additionally validated by μCT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20-49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint. Conclusion: CoMiCs represent a new form of structural change in the joints of patients with RA. While CoMiCs increase with age, RA patients develop such changes much earlier in life and already at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA. This article is protected by copyright. All rights reserved.

Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT)

OBJECTIVE The comparison between different techniques to quantify the 3-dimensional size of inflammatory bone erosions in rheumatoid arthritis(RA) patients. METHODS Anti-cyclic citrullinated peptide antibody(ACPA) positive RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the metacarpophalangeal joints (MCP). Erosions were measured by three different segmentation techniques: (1) manual method with calculation by half-ellipsoid formula, (2) semi-automated modified Evaluation Script for Erosions (mESE), and (3) semi-automated Medical Image Analysis Framework (MIAF) software. Bland & Altman plots were used to describe agreement between methods. Furthermore, shape of erosions was classified as regular or irregular and then compared to the sphericity obtained by MIAF. RESULTS A total of 76 erosions from 65 RA patients (46 females/19 males), median age 57 years, median disease duration 6.1 years and median disease activity score 28 of 2.8 units were analyzed. While mESE and MIAF showed good agreement in the measurement of erosion size, the manual method with calculation by half-ellipsoid formula underestimated erosions size, particularly with larger erosions. Accurate segmentation is particularly important in larger erosions, which are irregularly shaped. In all three segmentation techniques irregular erosions were larger in size than regular erosions (MIAF: 19.7 vs. 3.4mm3; mESE: 15.5 vs. 2.3mm3; manual = 7.2 vs. 1.52mm3; all p < 0.001). In accordance, sphericity of erosions measured by MIAF significantly decreased with their size (p < 0.001). CONCLUSION MIAF and mESE allow segmentation of inflammatory bone erosions in RA patients with excellent inter reader reliability. They allow calculating erosion volume independent of erosion shape and therefore provide an attractive tool to quantify structural damage in individual joints of RA patients.

Development of three-dimensional prints of arthritic joints for supporting patients’ awareness to structural damage

BackgroundRheumatoid arthritis (RA) and psoriatic arthritis (PsA) result in severe joint destruction and functional disability if left untreated. We aim to develop tools that help patients with RA and PsA to understand and experience the impact of inflammatory joint disease on the integrity of their (juxta-articular) bone and increase adherence to medical treatment. In this study, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to develop 3D prototypes of patients’ finger joints.MethodsHR-pQCT (XtremeCT, Scanco) measurements were performed in healthy individuals and patients with inflammatory joint disease, followed by a 3D print using the objet30 printer. Healthy participants (n = 10), and patients (n = 15 with RA and 15 with PsA) underwent a detailed, standardized interview with demonstration of printed joints.ResultsUtilizing HR-pQCT images of metacarpophalangeal (MCP) heads, high quality and exact 3D prints as prototypes were created. Erosions in different sizes and the trabecular network printed in detail were visualized, demonstrating structural reduction in arthritic vs. healthy bone. After demonstration of 3D prints (healthy vs. erosive joint, visual and haptic) 26/39 (66%) participants (including healthy volunteers) were deeply affected, often quoting “shock”. Of the patients with RA and PsA, 13/15 (86%) and 11/15 (73%), respectively, stated that they would rethink their attitude to medication adherence. More importantly, 21/24 patients with RA or PsA (87.5%) expressed that they would have wished to see such 3D prints during their first disease-specific conversations.ConclusionUsing arthro-haptic 3D printed prototypes of joints may help to better understand the impact of inflammatory arthritides on bone integrity and long-term damage.

Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures

Objectives Bone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in RA are undefined. This study aimed to define the impact of RA on the functional properties of bone, such as failure load and stiffness. Methods Micro-finite element analysis (µFEA) was carried out to measure failure load and stiffness of bone based on high-resolution peripheral quantitative CT data from the distal radius of anti-citrullinated protein antibody (ACPA)-positive RA (RA+), ACPA-negative RA (RA−) and healthy controls (HC). In addition, total, trabecular and cortical bone densities as well as microstructural parameters of bone were recorded. Correlations and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength as well as its relation to prevalent fractures. Results 276 individuals were analysed. Failure load and stiffness (both P<0.001) of bone were decreased in RA+, but not RA−, compared with HC. Lower bone strength affected both female and male patients with RA+, was related to longer disease duration and significantly (stiffness P=0.020; failure load P=0.012) associated with the occurrence of osteoporotic fractures. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (P=0.007) and sex (P<0.001) were independently associated with reduced biomechanical properties of bone in RA. Conclusion In summary, µFEA showed that bone strength is significantly decreased in RA+ and associated with fractures.

A comparative analysis of articular bone in large cohort of patients with chronic inflammatory diseases of the joints, the gut and the skin

Chronic inflammatory diseases are associated with bone loss. While the occurrence of systemic bone loss is well described in chronic inflammatory diseases, the impact of these conditions on articular bone has not been systematically investigated. Recent refinements in high-resolution CT assessment of the joints now allow the accurate measure of articular bone composition. In this study 476 subjects comprising healthy individuals and patients with anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA), ACPA-negative RA, Crohns disease (CD), ulcerative colitis (UC), psoriasis (PsO) and psoriatic arthritis (PsA) were subjected to high-resolution quantitative computed tomography (HR-pQCT) of the hand. Metacarpal heads were assessed for total, trabecular and cortical volumetric bone mineral density (vBMD). Only ACPA+RA, but not the remaining inflammatory diseases (ACPA-RA, CD, UC, PsO, PsA) showed significant (p < 0.001) loss of articular bone affecting both the trabecular and the cortical compartments. Age and body mass index were also associated with articular bone changes, the former with lower, the latter with higher articular bone mass. In multivariate models, presence of ACPA+RA was an independent factor for articular bone loss. Among chronic inflammatory diseases ACPA+RA is the most potent precipitator for articular bone loss pointing out the role of autoimmunity in the development of articular bone disease in the context of chronic inflammatory disease.

FRI0559 Biomechanical properties of radial bone are different between auto-antibody positive and negative rheumatoid arthritis

Background Functional properties of bone in rheumatoid arthritis (RA) are still not well characterised. Objectives This study aimed to define the impact of anti-citrullinated antibodies (ACPA) on biomechanical properties in RA. Methods Based on on high-resolution peripheral quantitative computed tomography (HR-pQCT) data from the distal radius of ACPA-positive RA (RA+), ACPA-negative RA (RA-) and healthy controls (HC) micro-finite element analysis (µFEA) was carried out to measure failure load and stiffness of bone.(1 Comparisons of µFEA parameters between groups was calculated and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength. Results A total of 276 subjects (96 RA+, 84 RA- and 96 HC) were analysed. Age and sex distributions were not significantly different between the three groups. In RA +but not in RA- failure load and stiffness were significantly decreased compared to HC (both p<0.001). Lower bone strength affected both female and male RA +patients and was related to longer disease duration. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (p=0.007) and sex (p<0.001) were independently associated with reduced biomechanical properties of bone in RA. Conclusions In summary, µFEA showed that bone strength is significantly decreased in RA +but not in RA- disease. Reference [1] Macneil JA, Boyd SK. Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method. Bone2008;42(6):1203–13. Disclosure of Interest None declared

SAT0628 Increase of cortical micro-channels (COMICS) as a new feature of structural damage in paients with rheumatoid arthritis

Background Bone damage in rheumatoid arthritis (RA) typically emerges at certain anatomical hotspots corresponding to the so-called “bare area”, an intra-articular region between the cartilage and the insertion site of the joint capsule (1,2). We hypothesized that this region exhibits certain micro-anatomical properties, which facilitates the emergence of bone erosions. Objectives To find the micro-structural correlate of the origin of bone erosions in the bare area of the human joint Methods Bare areas of human joints were analyzed for early microstructural changes by in-vivo high-resolution peripheral computed tomography (HR-pQCT). First, bare areas were exactly defined by scanning 6 cadaveric hands for localization of the bare area in the human metacarpal head. Bone lesions found in the cadaveric hand by HR-pQCT were additionally by super-resolution ex vivo micro-CT (μCT40). Then, number and distribution of the type of bare area bone lesion found in cadaveric study were analyzed in a cohort of 105 healthy individuals and 107 anti-citrullinated peptide (ACPA) positive RA patients with similar sex and age distribution. Results HR-pQCT combined with adaptive thresholding allowed the definition of a new type of bone lesions in the bare areas of the human joint termed “COMIC” standing for “cortical micro-channel”. Their existence in the bare area was additionally validated by microCT (Figure 1). RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20–49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint. Conclusions CoMiCs represent a new structural feature of the joint, which is characteristic for the bone of the bare area. COMICS at low level are also found in young healthy individuals but they significantly increase with age and particularly with RA. COMICs develop much earlier and much more pronounced in RA patients than in healthy individuals and therefore represent an interesting new early indicator for erosion development in ACPA positive RA patients. References Stach CM, Bauerle M, Englbrecht M, Kronke G, Engelke K, Manger B, et al. Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high-resolution computed tomography. Arthritis & Rheumatism. 2010;62(2):330–9. Simon D, Kleyer A, Stemmler F, Simon C, Berlin A, Hueber AJ,Haschka J, Renner N, Figueiredo C, Neuhuber W, Buder T, Englbrecht M, Rech J, Engelke K, Schett G. Age- and Sex-Dependent Changes of Intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis. J Bone Miner Res. 2016 Oct 27. doi: 10.1002/jbmr.3025. [Epub ahead of print]. Disclosure of Interest None declared

SAT0543 Accurate Determination of Periarticular Bone Composition in Healthy Individuals and Comparison To Acpa-Positive Rheumatoid Arthritis Patients

Background Periarticular bone loss is a typical finding in rheumatoid arthritis (RA) patients. However, this structural bone change is yet insufficiently characterized. Larger studies assessing periarticular bone composition in healthy controls (HC) and RA patients by high-resolution imaging have not been undertaken and have not been validated against standard measurement at the distal radius. Objectives To assess periarticular bone by high-resolution peripheral quantitative computed tomography (HR-pQCT) in the metacarpal heads and compare it with standard measurement in the distal radius in HC and anti-citrullinated peptide antibodies-positive (ACPA+) RA patients. Methods HR-pQCT (XtremeCT, Scanco, Switzerland) scans of the distal radius and of the metacarpal head 2 joints of HC and RA patients were performed. In contrast to previous studies the entire metacarpal head was assessed. After motion grading of the images by two independent readers, images with a motion grade more than 3 were excluded. A graphical objet (GOBJ) was generated and evaluated using the standard evaluation protocol for the radius provided by the manufacturer for both, the metacarpal head and the distal radius. In the last step, bone density values such as average bone density (D100 [mg HA/cm3]), bone volume/total volume (BV/TV), number of trabeculae (Tb N [1/mm])) were determined and compared between (i) the metacarpal head and the radius and (ii) between HC and RA patients. Results 222 subjects (110 HC and 112 RA) were analyzed. Sex and age distribution were balanced between HC (f/m: 58/52; 50.1±16.1 years) and RA patients (f/m: 53/59; 53.2±12.4 years; disease duration 9.2±8.7 years). Bone density in HC was 288.3±54.7 mg HA/cm3 in the distal radius and 294.4±43.3 mg HA/cm3 in the metacarpal head with significant correlation (ρ=0.583 (p<0.001)) (Fig1a, top row). Respective bone densities in RA patients were 269.8±49.6 mg HA/cm3 and 263.3±46.0 mg HA/cm3 with significant correlation (ρ=0.632 (p<0.001)) (Fig. 1a, bottom row). Similar correlations were found for BV/TV (HC: ρ=0.590, p<0.001, RA: ρ=0.687, p<0.001) and Tb N (HC: ρ=0.576, p<0.001, RA: ρ=0.705, p<0.001). Comparing bone densities between HC and RA patients we found significant bone loss in both the metacarpal head (p<0.001, U=3834.5, Z=-4.860) and the distal radius (p=0.018, U=2700.5, Z=-2.357) in RA patients. Examples of measurements in the metacarpal heads of HC and RA patients are shown in Figure 1b. Conclusions In this large study, we show that the assessment of periarticular bone structure in metacarpal heads is feasible and correlates well with standard measurement in the distal radius. Furthermore, we show significant bone loss in RA patients as compared to HC in both anatomical sites. Disclosure of Interest None declared