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Objective To investigate whether methotrexate (MTX) use is associated with bone mineral density (BMD) in patients with polymyalgia rheumatica (PMR) and various forms of vasculitis. Methods Rh-GIOP is a cohort study designed to evaluate bone health in patients with inflammatory rheumatic diseases. This cross-sectional analysis assessed the baseline visits of all patients with PMR or any kind of vasculitis. Following univariable analysis, multivariable linear regression analysis was performed. The lowest T-score of either the lumbar spine or the femur was chosen as the dependent variable to examine the relationship between MTX use and BMD. These analyses were adjusted for a variety of potential confounders, including age, sex, and glucocorticoid (GC) intake. Results Of 198 patients with PMR or vasculitis, 10 patients were excluded for very high GC dose (n = 6) or short disease duration (n = 4). The remaining 188 patients had the following diseases: PMR 37.2%, giant cell arteritis 25.0%, granulomatosis with polyangiitis 16.5%, followed by rarer diseases. The mean age was 68.0 ± 11.1 years, mean disease duration was 5.58 ± 6.39 years, and 19.7% had osteoporosis by dual x-ray absorptiometry (T-score ≤ −2.5). 23.4% were taking MTX at baseline with a mean dose of 13.2 mg/week (median: 15 mg/week). 38.6% of those used a subcutaneous preparation. MTX users had similar BMD compared to non-users (minimum T-scores −1.70 (± 0.86) versus −1.75 (± 0.91), respectively; p = 0.75). There was no statistically significant dose–response relationship: neither current nor cumulative dose were associated with BMD in unadjusted or adjusted models (current dose: slope −0.02; −0.14 to 0.09; p = 0.69; cumulative dose: slope −0.12; −0.28 to 0.05; p = 0.15). Conclusion In the Rh-GIOP cohort, MTX is used in about a quarter of patients with PMR or vasculitis. It is not associated with BMD levels.

Als kleinwüchsige Rollstuhlfahrerin bin ich in meiner Mobilität durch verschiedenste Hindernisse mehr oder weniger stark eingeschränkt. In diesem Artikel werde ich beschreiben, wie sich die Ausbildung für Bibliothekarinnen und Bibliothekare mit körperlichen Einschränkungen gestaltet. Ich schildere meine persönlichen Erfahrungen, die ich bei den Lehrgängen sowohl im ehrenamtlichen als auch im wissenschaftlichen Bereich, bei den dafür erforderlichen Praktika und Projekten sowie dem damit verbundenen bürokratischen und organisatorischen Aufwand gemacht habe. Abschließend werde ich auch auf die Möglichkeiten zur bibliothekarischen Weiterbildung kurz eingehen.

X-ray is the fundamental imaging technique in both diagnosis and follow-up of rheumatic diseases. As patients often require sequential X-rays over many years, dose reduction is of great importance. New advanced noise reduction algorithms allow for a dose reduction of up to 50%. The aim of this study was to evaluate whether quality of low-dose images is non-inferior to standard-dose images and, therefore, application of this technique is possible in the context of imaging of rheumatic diseases. A total of 298 patients with known or suspected rheumatic disease were enrolled prospectively into this study, separated into three consecutive groups: 80%, 64% and 50% tube charge reduction. All patients received imaging of one hand (laterality randomly assigned) with low-dose technique and imaging of the contralateral hand with standard-dose protocol. Images were evaluated by two independent readers who scored (on a scale of 1–5) the visualization of bony cortex, trabeculae and joint spaces of fingers and wrist separately. Additionally, soft tissue and overall contrast were evaluated on the same scale. Overall image quality (expressed by mean sum score out of 40) of the 50% low-dose images was 31.52 (SD 1.94) vs. 31.66 (SD 1.82) for standard images (p = 0.068). Bony contours as well as trabeculae were equally well visualized in both image sets. Median scores for soft tissue visualization was slightly lower for low dose compared to standard images [4 (IQR 3.5–4) vs. 4 (IQR 3.88–4); p = 0.001]. Overall image quality of low-dose images was not inferior to standard-dose images. Therefore, the application of low-dose technology based on advanced noise estimation algorithms in the context of imaging of rheumatic diseases is possible.

Background: Glucocorticoids (GCs) can cause osteoporosis (OP). Prior observational research on bone density and the effects of GCs in polymyalgia rheumatica (PMR) and vasculitides is scarce and inconclusive. Methods: Rh-GIOP is a prospective cohort study of bone health in patients with inflammatory rheumatic diseases. In this cross-sectional baseline analysis, we focused on patients with PMR and different forms of vasculitides. Multivariable linear regression was used to model the effect of current and cumulative GC intake on the minimum T-score at any site (mTs; at either lumbar spine or hip), with comprehensive adjustment for confounders. In separate models, GCs were modelled both as continuous and categorical predictors. Sensitivity analyses, stratifying by measurement site and disease, were conducted. Results: A total of 198 patients, with a mean age of 67.7 ± 11.4 years and a mean disease duration of 5.3 ± 6.3 years, were included. Most patients suffered from PMR (36%), giant cell arteritis (26%) or granulomatosis with polyangiitis (17%). Women comprised 66.7% of the patients, and 87.4% were currently taking GCs. The mean CRP was 13.2 ± 26.1 mg/L. OP diagnosed by dual energy X-ray absorptiometry (DXA) (T-score ≤ −2.5) was present in 19.7% of the patients. While 88% were taking vitamin D supplements, calcium supplementation (4%) and treatment with anti-resorptive agents (17%) were relatively infrequent. Only 7% had a vitamin D deficit. Neither current (β(continuous model) = −0.01, 97.5% CI –0.02 to 0.01; p(all models) ≥ 0.49) nor cumulative (β(continuous model) = 0.01, 97.5% CI −0.04 to 0.07; p(all models) ≥ 0.35) GC doses were associated with mTs in any model. CRP was not associated with mTs in any model (p(all models) ≥ 0.56), and no interaction between CRP and GC intake was observed (p for interaction(all models) ≥ 0.32). Across all analyses, lower body mass index (p(all models) ≤ 0.01), history of vertebral fractures (p(all models) ≤ 0.02) and proton-pump inhibitor intake (p(all models) ≤ 0.04) were associated with bone loss. Sensitivity analyses with femoral neck and lumbar spine T-scores as dependent variables led to similar results as the analysis that excluded patients with PMR. Conclusions: In this cohort of PMR and vasculitides, we found a similar prevalence of OP by DXA to the overall elderly German population. Vitamin D supplementation was very common, and vitamin D insufficiency was less frequent than expected in Germans. There was no association between current or cumulative GC intake, CRP and impaired bone density. Proton-pump inhibitors seem to be a major, but somewhat neglected, risk factor for OP and should be given more attention. Our findings require confirmation from longitudinal analyses of the Rh-GIOP and other cohorts.

To evaluate the ability of dual-energy computed tomography (DECT) to improve diagnostic discrimination between gout and other crystal arthropathies such as calcium pyrophosphate deposition disease (CPPD) of the wrist in a clinical patient population. This retrospective case-control study included 29 patients with either gout (case group; n = 9) or CPPD (control group; n = 20) who underwent DECT of the wrist for clinically suspected crystal arthropathy. Color-coded urate and enhanced calcium as well as virtual 120 kVe blended images were reconstructed from the DECT datasets. Two independent and blinded readers evaluated each reconstructed dataset for the presence of depositions in 17 predefined regions. Additionally, a global diagnosis was made first for 120 kVe images only, based solely on morphologic criteria, and subsequently for all reconstructed images. Sensitivity for the global diagnosis of gout was 1.0 (95% CI 0.63–1) for both DECT and 120 kVe images with specificities of 0.70 (95% CI 0.46–0.87) for DECT and 0.80 (95% CI 0.56–0.93) for 120 kVe images. Color-coded DECT images did not detect more depositions than monochrome standard CT images. Discrimination of crystal arthropathies of the wrist is limited using DECT and primarily relying on color-coded images. Evaluation of morphologic criteria on standard CT images is essential for accurate diagnosis.

Objective: To evaluate the ability of fluorescence optical imaging (FOI) Xiralite® in the prediction of RTX re-therapy in rheumatoid arthritis (RA) patients - in comparison to clinical, laboratory and musculoskeletal ultrasound (US) parameters.Patients and methods: Patients with established RA were prospectively followed over one year by DAS28, patient’s global disease activity (VAS 0-100 mm), CRP and ESR, US7 score and FOI in phases 1-3 and automatically generated PrimaVistaMode (PVM) at baseline (before RTX) and after 3, 6, and 12 months. The need for RTX re-therapy was decided by the treating rheumatologist – blinded to imaging data.Results: 31 patients (female 77.4%, mean age 60.1±11.4, mean disease duration 14.9±7.1 years) were included. Fourteen patients (45.2%) received RTX re-therapy within 12 months. In the group with RTX re-therapy, FOI in PVM mode was the only parameter that presented significant increase over time (beta 0.40, CI 0.08-0.71; p=0.013) – compared to the group without re-therapy. In the prediction model via ROC analysis, FOI in PVM reached the highest values of all imaging, clinical and laboratory parameters for the prediction of re-therapy over one year with an area under the curve (AUC) of 0.78 (OR 0.84, CI 0.72;0.98, p=0.031). US7 GS synovitis score revealed similar predictive power with an AUC of 0.73 (p=0.049).Conclusion: US7 GS synovitis score and FOI in PVM are able to discriminate between patients with and without need for RTX re-therapy better than clinical and laboratory parameters.

Objectives: The effects of aging such as osteophyte formation, acral shape changes, cortical tunneling, and bone porosity as well as enthesophytes can be studied in the X-rays of hands. However, during the interpretation of radiographs of the hands, misinterpretation and false-positive findings for psoriatic arthritis often occur because periosteal proliferations of the phalanges are overinterpreted and too little is known about enthesophytes of the phalanges in this area. Method: It included a total of 1153 patients (577 men, 576 women) who presented themselves to the emergency department and received a radiography of their right hand to exclude fractures. The Osseographic Scoring System was used in a modified form to record osteophytes and enthesophytes. A linear regression model for periosteal lesions was computed with age, sex, osteophytes, and global diagnosis as covariables. The inter-reader agreement was assessed using ICC (two-way mixed model) on the sum scores of osteophytes and periosteal lesions. Results: Overall, men exhibited more periosteal lesions, demonstrated by a higher mean sum score of 4.14 vs. 3.21 in women (p = 0.008). In both sexes, the second and third proximal phalanx were most frequently affected by periosteal lesions, but the frequencies were significantly higher in men. The female sex was negatively associated with an extent of periosteal lesions with a standardized beta of −0.082 (p = 0.003), while age and osteophytes were positively associated with betas of 0.347 (p < 0.001) and 0.156 (p < 0.001), respectively. The distribution of osteophytes per location did not differ between men and women (p > 0.05). The inter-reader agreement was excellent for periosteal lesions with ICC of 0.982 (95%CI 0.973–0.989, p < 0.001). Conclusions: Special care should be taken not to confuse normal periosteal changes in aging with periosteal apposition in psoriatic arthritis.

Zusammenfassung Hintergrund Patient-reported-outcomes (PROs) haben einen zunehmenden Einfluss auf die unmittelbare Therapieentscheidung des Arztes in der klinischen Praxis. Zielstellung Überprüfung der Integration und des Nutzens von elektronisch erhobenen PROs per ScoreCheck Rheuma®-App (SCR App) im klinischen Praxisalltag der rheumatologischen Fachambulanz (Dispensaire) der Charité - Universitätsmedizin Berlin in Hinblick auf Praxistauglich, Patientenakzeptanz und medizinischen Mehrwert. Patienten und Methoden N=190 Patienten (63% weiblich, mittleres Alter: 55 Jahre, min 23-max 82; Diagnosen: 52,9% Rheumatoide Arthritis, 28,6% Spondyloarthritis, 9,3% Kollagenosen, 3,6% Vaskulitis, 5,6% sonstiges) sowie 3 medizinische Fachangestellte (MFA) und 3 Ärzte (Rheumatologen) haben an diesem Pilotprojekt teilgenommen. Die folgenden PROs wurden elektronisch mittels SCR App von den eingeschlossenen Patienten ausgefüllt: FFbH (Funktionsfragebogen Hannover), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) und BASFI (Bath Ankylosing Spondylitis Functional Index) sowie ein Fragebogen zur Selbsteinschätzung. Zusätzlich wurde für jeden eingeschlossenen Patienten je ein Beurteilungs-Protokoll vom Patienten selbst, von der zuständigen MFA und vom betreuenden Arzt ausgefüllt. Ergebnisse Von den 190 teilnehmenden Patienten gaben 147 (77%) an, Vorerfahrungen mit Touchpad-Geräten zu haben. 96% der Patienten fühlten sich außerdem gut bis sehr gut in die Bedienung des iPADs und der SCR App durch die MFAs eingewiesen und fanden das Ausfüllen der Fragebögen auf dem iPAD einfach; Schwierigkeiten, wie z. B. mit der Schriftgröße, der Handhabung, usw. wurden nur von 10% der Patienten angegeben. Immerhin 74% der Patienten wünschten sich den vermehrten Einsatz elektronischer Hilfsmittel beim Arztbesuch und 75% bevorzugten den Einsatz des iPADs gegenüber dem Ausfüllen der Fragebögen auf Papier. Die MFAs gaben in über 80% der Fälle an, dass die Patienten die Fragebögen zu den PROs ohne oder mit nur wenig Hilfe selbstständig ausfüllen konnten. In ca. 2/3 der Fälle sahen die MFAs Vorteile durch die Anwendung der SCR App sowohl bezüglich der Qualität der Patientenbetreuung als auch bezüglich der Erfassung der Funktionsscores. Die Ärzte sahen in 2/3 der Fälle eher keine Zeitersparnis durch den Einsatz des iPADs. In 78% der Fälle konnte der Patientenscore in das Arzt-Patienten-Gespräch eingebracht werden, jedoch sparte die Anwendung der SCR App nur in 50% der Fälle Zeit im Praxisalltag. Die Ärzte sahen v. a. Vorteile bezüglich der Anamneseerhebung und der Therapieempfehlungen. Schlussfolgerung Insgesamt zeigt das vorgestellte Pilotprojekt zur Anwendung und Integration der SCR App eine gute Resonanz bei den Patienten, MFAs und Ärzten. Die Arztbewertung ergibt, dass durch die SCR App bei jedem zweiten Patienten ein Vorteil bei der Therapieempfehlung gesehen wurde.

A Correction to this paper has been published: 10.1007/s00256-021-03833-5

Background Reports on the prevalence of osteoporosis, osteoporotic fractures and risk factors for osteoporosis in patients with psoriasis (PSO) or psoriatic arthritis (PSOA) are scarce, and the published results on this are, at least in part, contradictory. [1] Despite the fact that IL-17 is involved in bone homeostasis under both physiologic and pathologic conditions, there is no detailed knowledge of the direct and indirect impact an IL-17 antagonist like secukinumab (SEC) has on bone mineral density (BMD). Objectives Rh-GIOP (ClinicalTrials.gov Identifier NCT02719314) is an ongoing prospective study monitoring glucocorticoid (GC)-induced osteoporosis of rheumatic patients, established in 2015 at the Charite University Hospital. For this analysis, clinical data and bone mineral density data measured by dual x-ray absorptiometry (DXA) of 936 patients with inflammatory rheumatic diseases provided the basis. The main objective of this cross-sectional analysis was to evaluate the prevalence of osteoporosis and the frequency of fractures in patients with PSO or PSOA. Additionally, patients treated with secukinumab were compared to those with methotrexate (MTX) with regard to BMD, fracture incidence, physical activity, and back pain Methods We analyzed the initial visit of 103 patients with PSO (n= 31, 74% female) or PSOA (n=72, 64% female). Descriptive analyses were performed, and values are displayed as means and standard deviations. For subgroup analyses non-parametric tests were used. Results The prevalence of osteoporosis in our patient group (mean age: 62±10 years; 67% female; mean disease duration: 17±13 years) was 19%. The prevalence of osteopenia was 26%, 34% (n=35) reported peripheral fragility fractures, and 11% (n=11) had vertebral fractures in history. Regular physical activity was reported by 41% (n=42), while 53% (n=55) suffered from movement restrictions. Back pain was present in 68% (n=70) of patients with a mean numeric rating scale of 5 (NRS; 0-10). SEC was used by 18% (n=19), and MTX by 42% (n=43, 25% sc, 13% oral, 4% unknown), respectively. Eight percent had a combination therapy of MTX and SEC. Twenty-seven percent used GC and/or other biologics/conventional disease modifying antirheumatic drugs (DMARDs). Mean glucocorticoid cumulative dose (GCCD) was 12.8±22.0g. Patients with SEC showed a significantly longer disease duration (median: 24 years vs. 13 years) compared to MTX, but showed no other differences in baseline-characteristics or risk factors. T-Scores of both femora were significantly higher in the MTX versus the SEC group. We could not find significant differences between these groups with regard to physical activity, back pain, movement restriction, fracture rates or GCCD. Twenty-five percent of the MTX users and 27% of the patients in the SEC group additionally had GC while; in contrast to no patient in the combination group. Conclusion The prevalence of osteoporosis in patients with PSO or PSOA was found to be as high as in the normal population. However, there was a high frequency of peripheral fragility, but not vertebral fractures. Patients with PSO or PSOA patients treated with SEC had a longer disease duration and lower hip BMD, but showed no differences in back pain, physical activity or movement restrictions compared to MTX users. Funding: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi. References [1] Frediani, B., et al., Bone mineral density in patients with psoriatic arthritis. J Rheumatol, 2001. 28(1): p.138-43. Disclosure of Interests Desiree Freier: None declared, Edgar Wiebe Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, Chugai, Hexal AG, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., Kim Zeiner: None declared, Robert Biesen: None declared, Thomas Buttgereit: None declared, Sandra Hermann: None declared, Frank Buttgereit: None declared

Background The Charite Rh-GIOP is a prospective study of disease- & bone-related data from patients with chronic inflammatory diseases treated with glucocorticoids (GCs). The Glucocorticoid Toxicity Index app (GTI 2.0) measures changes in GC-associated morbidity. The GTI captures improvement as well as worsening in GC toxicity, and consists of two subscores. With the Cumulative Worsening Score (CWS), only worsening toxicities are counted. The CWS is always a positive number or, if no toxicity has occurred, 0. With the Aggregate Improvement Score (AIS), both improvement and worsening are considered. If the overall GC toxicity has improved, the AIS is negative. Objectives To evaluate the GTI in a prospective cohort of GC-treated vasculitis patients. Methods Vasculitis patients were included if starting GC or having a flare requiring increased GC. Doses were calculated in prednisone (PRED) equivalents. Nearly all patients had received GC (often for years) baseline (V1). Data for the 9 GTI domains were collected at V1 and follow-up (V2). These included: medications for hypertension, hyperglycemia, and hyperlipidemia; body mass index; bone mineral density; and data pertaining to muscle strength, skin toxicity, neuropsychiatric effects, and infections. Data for the blood pressure, glucose control, and lipid domains were inferred from treatment changes. We used multivariate logistic regression models to examine the relationship of PRED dose to the likelihood of CWS worsening and AIS improvement. Results 37 patients (25F; 12M) of mean age 66.6 years (range: 40.5-81.7) were included. Diagnoses: GCA (n=7), PMR (14), AAV (10), EGPA (4), and PAN (2). Thirty-four (92%) patients had changes in GC toxicity between V1-V2. The mean CWS & AIS were 34.8 and 11.1, respectively. Twenty-eight patients (76%) had CWSs >0, indicating worsening toxicity. Twenty-one (57%) had AISs >0, also consistent with overall GC toxicity worsening. However, 13 (35%) had negative AISs, indicating improvements in GC toxicity. BMD measurements worsened by at least 3% in 16 (43%) patients and improved by at least 3% in 9 (24%). Cumulative PRED doses correlated strongly with the CWS. For every 1000mg of PRED between V1 & V2, the risk of CWS increase – worsening of GC toxicity – rose by 79% (Table 2). Conclusion The GTI captured changes in GC toxicity over time well, both improvement and worsening. Cumulative PRED dose correlated strongly with increase in the Cumulative Worsening Score. Acknowledgement Rh-GIOP is supported by a joint funding of Amgen, Bristol-Meyers Squibb, MS, Celgene, Chugai, Generic Assays, Glaxo-Smith Kline, Hexal AG, Horizon, Lilly, Medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi. Disclosure of Interests Lisa Ehlers: None declared, Edgar Wiebe Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, Chugai, Hexal AG, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., Desiree Freier: None declared, Sandra Hermann: None declared, Eli Miloslavsky: None declared, Yuqing Zhang: None declared, Frank Buttgereit: None declared, John H. Stone Grant/research support from: F. Hoffmann-La Roche, Genentech, Xencor, Consultant for: Chugain, F. Hoffmann-La Roche, Genentech, Xencor

Dual-energy computed tomography detects tophi in patients with chronic gout. However, other information that can be obtained from the same scan is not the focus of the current research, e.g., the detection of bone marrow edema (BME) using virtual bone marrow imaging (VBMI). The aim of this study was to evaluate if BME in patients with acute arthritis can be detected with VBMI using magnetic resonance imaging (MRI) as the standard of reference.This retrospective study included 11 patients who underwent both MRI and dual-energy computed tomography (mean interval of 40 days). BME in MRI (standard of reference) and VBMI was judged independently by two different blinded readers. φ-correlation coefficient and Cohen's κ were performed for statistical analysis. Approval was waived by the IRB.Two patients with a final diagnosis of RA and one with septic arthritis showed osteitis on MRI and VBMI. However, in each case, there were individual bones identified with osteitis on MRI but not VBMI. Three additional patients with the final diagnosis of RA were identified correctly as negative for BME. There was a good correlation between both modalities (φ = 0.8; κ = 0.8). Inter-rater reliability was excellent for both modalities (κ = 0.9).We have shown that detecting osteitis using VBMI is feasible in patients with inflammatory arthritis. Further studies are needed on larger, more-targeted populations to better define the indications, accuracy, and added value of this technique.

Background:The prevalence of osteoporosis in inflammatory rheumatic diseases such as psoriatic arthritis (PsA) has not been sufficiently clarified yet, and the data in the literature are heterogeneous. In addition, it is still unclear to what extent patients with PsA differ in terms of bone density from patients with other forms of spondyloarthritis such as ankylosing spondylitis (AS).Objectives:In an interim analysis of the Rh-GIOP Study (ClinicalTrials.gov IdentifierNCT02719314), we observed that PsA patients demonstrated more frequently normal bone density than any other patient group analyzed (suffering from e.g. rheumatoid arthritis or systemic sclerosis). The main objective of this investigation was to compare bone density data from patients with PsA and AS, as both diseases belong to the spondyloarthritis group. 1100 patients with inflammatory rheumatic diseases provided the basis of Rh-GIOP, a prospective study monitoring glucocorticoid (GC)-induced osteoporosis in patients with rheumatic diseases. Rh-GIOP was established in 2015 at the Charité University Hospital. Bone mineral density data were measured by dual x-ray absorptiometry (DXA).Methods:92 patients with PsA (65% female) were compared with 51 patients suffering from AS (35% female). Potential risk and protective factors (e.g. data on GC treatment, anti-rheumatic therapy), laboratory parameters (e.g. Vitamin D, alkaline phosphatase, calcium and inflammatory markers) and functional status (e.g. Health Assessment Questionnaire, sporting activities, back pain) were compared between these groups. Statistical analysis was performed descriptively using mean and standard deviation, t-tests for metric variables, and chi-square tests for nominal variables. Due to the heterogeneous gender distribution, an additional statistical matching was performed to compare patients matched by age and gender.Results:Patients with PsA displayed significantly higher minimal T-scores than patients with AS (p=0.003) even though patients with AS were younger and more often male (pConclusion:Our results demonstrate that patients with PsA display higher bone density compared to age and gender matched patients with ankylosing spondylitis. Possible influencing factors could be the higher frequency of csDMARD use, higher BMI or the lower frequency of back pain in PsA patients. Multivariate tests and additional biomarker investigations in larger cohorts are necessary to corroborate these findings and to identify underlying pathogenic differences which could serve for an explanation.Disclosure of Interests:Desiree Freier: None declared, Edgar Wiebe: None declared, Robert Biesen: None declared, Thomas Buttgereit: None declared, Sandra Hermann: None declared, Timo Gaber: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Background:Osteoporosis is a skeletal disease characterized by the loss of bone density resulting in an increased fracture risk. Female sex, advanced age, Caucasian ancestry, previous history of fractures, menopause and certain genetic factors predispose for osteoporosis. In addition, recent studies could prove that chronic inflammatory diseases such as Rheumatoid Arthritis (RA) and long-term treatment with higher doses of glucocorticoids (GCs) represent independent risk factors for the development of osteoporosis. On the other hand, the intake of vitamin D, a calcium-rich diet and physical exercise can be protective. Data describing the prevalence of osteoporosis in patients with other rheumatic diseases like psoriatic arthritis (PsA) are lacking.Objectives:We compared the prevalence of osteopenia and osteoporosis in patients with RA and PsA, respectively, based on data obtained from our ongoing prospective monocentric study Rh-GIOP investigating glucocorticoid (GC)-induced osteoporosis in patients with different rheumatic diseases (NCT02719314).Methods:Bone mineral density data measured by dual x-ray absorptiometry (DXA) in patients with PsA (n=92) were compared with data measured in 92 age- and gender-matched patients with RA. The results were analysed with respect to clinical and laboratory parameters such as data on GC treatment (frequency, duration defined as start of treatment until timepoint of measurement, actual and cumulative dose), csDMARD and bDMARD (including as well tsDMARDs) therapy, serological parameters (Vitamin D, alkaline phosphatase, calcium, inflammatory markers and rheumatoid factor) and functional status (e.g. Health Assessment Questionnaire (HAQ), sporting activities). Statistical analyses were performed descriptively using mean and standard deviation, t-tests for metric variables, and chi-square tests for nominal variables. For subgroup analyses with less than 30 patients per group, tests for non-normally distributed data were used due to the lower test power.Results:RA patients showed significantly lower means of bone density values (minimal T-score, p=0.03) than PsA patients leading to a higher frequency of osteopenic bone densities (pConclusion:The lower bone density in RA patients seems not to be fully explained by higher GCCD, disease duration or higher levels of inflammation. However, RA patients had a higher frequency of current GC intake. Additionally, differences in bone density between the two groups could be related to the higher number of bDMARD therapies in PsA patients, but further investigations like multivariate analyses with higher numbers of patients are necessary. Furthermore there is more need for research on possible molecular and genetic factors in PsA, which are protecting from low bone density.Disclosure of Interests:Desiree Freier: None declared, Edgar Wiebe: None declared, Robert Biesen: None declared, Thomas Buttgereit: None declared, Sandra Hermann: None declared, Timo Gaber: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Background:Rheumatoid arthritis (RA) is associated with increased systemic bone loss, leading to a high risk for fragility fractures. Especially anti-citrullinated protein antibody (ACPA) positivity is considered a risk factor for local bone erosions and systemic bone loss1.Objectives:The purpose of this study was to compare ACPA positive versus ACPA negative RA patients in terms of the prevalence of osteoporosis and fragility fractures and to identify differences in underlying risk factors that influence bone health.Methods:Rh-GIOP is an ongoing prospective observational study collecting and analyzing disease- and bone-related data from patients with chronic rheumatic diseases or psoriasis treated with glucocorticoids (GC). In this cross-sectional analysis, we performed a matched-pair analysis, matching 114 ACPA positive to 114 ACPA negative RA patients according to age (5-year-steps), sex, and body mass index (BMI, 2-unit-steps). Descriptive analyses were performed, with values displayed as mean ± standard deviation for continuous variables. Non-parametric tests were used at a two-sided significance level of 5% to compare differences in underlying and potential risk factors without adjustment for multiple testing.Results:At same mean age (63.9 ±10.2 years) and BMI (27.9 ±5.6kg/m2), the matched groups had a female proportion of 82.5%. APCA positive patients had a significantly longer mean disease duration (13.9 vs 9.9 years, pConclusion:In a cross-sectional analysis of our cohort, the prevalence of osteoporosis and fragility fractures was similar between ACPA positive and ACPA negative RA patients, despite longer disease duration and GC-treatment in ACPA positive patients. This is remarkable since it implies that ACPA negative patients are at a similar risk for osteoporosis and associated fractures. Optimal management of disease activity with or without GCs may represent a mainstay in preventing disease-related comorbidities such as osteoporosis.References:[1]Steffen, U., Schett, G., & Bozec, A. (2019). How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis. Frontiers in immunology, 10, 1483. doi:10.3389/fimmu.2019.01483Disclosure of Interests:Edgar Wiebe: None declared, Desiree Freier: None declared, Dörte Huscher: None declared, gloria dallagiacoma: None declared, Robert Biesen: None declared, Sandra Hermann: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Background:Rheumatic diseases are associated with increased systemic bone loss and fracture risk related to chronic inflammation, disease-specific, general and demographic risk factors as well as treatment with glucocorticoids (GC). Yet, there is evidence that GCs may, by adequately suppressing systemic inflammation, also have a positive effect on bone mineral density (BMD) and fracture risk1.Objectives:The purpose of this study was to investigate the prevalence of osteoporosis and fragility fractures in patients with inflammatory rheumatic diseases and to analyze the impact that treatment with GCs, other known risk factors and preventive measures have on bone health in these patients.Methods:Rh-GIOP is an ongoing prospective observational study collecting and analyzing disease- and bone-related data from patients with chronic inflammatory rheumatic diseases and psoriasis treated with GCs. In this cross-sectional analysis, we evaluated the initial visit of 1091 patients. A multivariate linear regression model with known or potentially influential factors adjusted for age and sex was used to identify predictors of BMD as measured by dual-energy X-ray absorptiometry (DXA). Multiple imputation was applied for missing baseline covariate data.Results:In the total cohort of 1091 patients (75% female of which 87.5% were postmenopausal) with a mean age of 62.1 (±13.2) years, the prevalence of osteoporosis by DXA was 21.7%, while fragility fractures have occurred in 31.2% of the study population (6.7% vertebral, 27.7% non-vertebral). Current GC therapy was common (64.9%), with a median daily dose of 5.0mg [0.0;7.5], a mean life-time total GC dose of 17.7g (±24.6), and a mean GC therapy duration of 7.8 years (±8.5). Bisphosphonates were the most commonly used anti-osteoporotic drug (12.6%).Multivariate analysis showed that BMD as expressed by the minimum T-Score at all measured sites was negatively associated with higher age, female sex and menopause as well as Denosumab and Bisphosphonate treatment. A positive association with BMD was found for body mass index as well as current and life-time (cumulative) GC dose. While comedication with proton-pump-inhibitors significantly predicted low bone mass, concomitant use of non-steroidal anti-inflammatory drugs showed a positive association with BMD. Of the measured bone-specific laboratory parameters, higher alkaline phosphatase levels were determinants of low DXA-values, while the association was positive for gamma-glutamyltransferase.BMD was neither predicted by duration of GC treatment nor by treatment with disease modifying anti-rheumatic drugs.Predictive variables for BMD differed at the respective anatomical site. While treatment with Denosumab predicted low bone mass at the lumbar spine and not at the femoral neck, the opposite was true for health assessment questionnaire (HAQ) score. Current and life-time GC-dose as well as direct sun-exposure of more than 30 minutes daily were positively associated with bone mass at the femoral sites only.Conclusion:This cross-sectional analysis of a prospective cohort study quantified the prevalence of osteoporosis and identified predictive variables of BMD in patients with rheumatic diseases.Multivariate analyses corroborated low BMD to be predicted by traditional factors like age, female sex and menopause but showed current and well as life-time GC dose to be positively associated with BMD in our cohort of patients with chronic inflammatory rheumatic diseases. This suggests that optimal management of disease activity with GCs might be beneficial in order to avoid bone loss due to inflammation.References:[1]Güler-Yüksel et al. “Glucocorticoids, Inflammation and Bone.” Calcified Tissue International (January 08 2018).Disclosure of Interests:Edgar Wiebe: None declared, Desiree Freier: None declared, Dörte Huscher: None declared, Robert Biesen: None declared, Sandra Hermann: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Background Rheumatoid arthritis (RA) is associated with increased systemic bone loss, leading to a high risk for fragility fractures. The etiology of increased fracture risk in RA is multifactorial and comprises next to general risk factors also RA-specific risks, most prominently chronic inflammation, seropositivity and glucocorticoid (GC) use1. Yet, there is evidence that GCs may, by adequately suppressing systemic inflammation, also have a positive effect on BMD and fracture risk in RA2. Objectives The purpose of this study was to investigate the prevalence of osteoporosis and fragility fractures in RA patients and to characterise, among other risk factors, the role of GC dose, cumulative dose (GCCD) and duration as well DMARD treatment on bone health. Methods Rh-GIOP is an ongoing prospective observational study collecting and analysing disease- and bone-related data from patients with chronic rheumatic diseases treated with GCs. In this cross-sectional analysis, we evaluated the initial visit of 238 patients with RA. Descriptive analyses were performed, with values displayed as mean/standard deviation and median/range for continuous variables. For subgroup analyses, non-parametric tests were used. Results Of 238 patients with RA (79.4% women, mean age: 63.6±12.5 years), 155 were seropositive and 83 seronegative. Seronegative patients were numerically older (66.8±12.1 vs 61.8±12.1 years) and more often in menopause (78.3% vs 61.8%, ns) than seropositive, while the latter had longer disease duration (median: 4.0 vs 11.0 years, p=0.03). Overall, osteoporotic BMD was more frequent at femoral sites, with 21% of patients having T-Scores All patients received GCs (mean dose: 5.0±6.8 mg, mean GCCD 15.1±19.3 g, mean duration 7.7±8.2 years) with seropositive patients having numerically higher GCCD, longer duration of GC therapy and more often current GC doses above >10 g/day. Biological DMARDs were more frequently used in seropositive patients (n=20;24.1% vs n=67;43.2%, p=0.02). Anti-osteoporotic therapies between both groups did not differ. Neither current GC doses nor GCCD nor DMARD therapy had a statistically significant and independent effect on BMD or fragility fractures in either RA group. Conclusions Osteoporosis and fragility fractures remain a challenge in the management of RA, being determined by multiple interacting factors. Our data confirm that GCs may not per se increase fracture risk and decrease BMD in RA but rather, that optimal management of disease activity with or without GCs may be beneficial to bone health. Interestingly however, despite higher cumulative GC doses and duration, seropositive RA patients did not have lower BMD or higher prevalence of fragility fractures compared to seronegative patients. Further prospective data is warranted to better characterise the role of GCs and DMARDs in regard to osteoporosis and fracture risk in RA patients. References [1] Briot K, et al. ”Inflammatory Diseases and Bone Fragility.”Osteoporosis International2017December 1;28(12):3301–14. [2] Guler-Yuksel, et al. ”Glucocorticoids, Inflammation and Bone.”Calcified Tissue International2018January 8. Disclosure of Interest E. Wiebe Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., R. Biesen Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., K. Zeiner Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., D. Freier Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., S. Hermann: None declared, G.-R. Burmester: None declared, F. Buttgereit Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche.

Background Reports on the prevalence of osteoporosis, osteoporotic fractures and risk factors for osteoporosis in patients with Psoriasis or Psoriasisarthritis are scarce, and the published results on this are, at least in part, contradictory. Additionally, there is no firm understanding of the impact of potential risk factors such as smoking and low Vitamin D (Vit D) levels have on the occurrence of osteoporotic fractures in this patient group. Objectives Rh-GIOP is an ongoing prospective study monitoring glucocorticoid (GC)-induced osteoporosis of rheumatic patients, established in 2015 at the Charite University Hospital. To date, the database comprises clinical data and bone mineral density data measured by dual x-ray absorptiometry (DXA) of 592 patients with inflammatory rheumatic diseases. (ClinicalTrials.gov Identifier NCT02719314) The objective of this cross-sectional analysis was to evaluate the prevalence of osteoporosis and frequency of fractures in patients with Psoriasis (PSO) or Psoriasisarthritis (PSOA). Additionally, smoking and Vit D status were investigated as possible risk factors for low BMD. Methods We evaluated the initial visit of 55 patients with PSO (80% female) or PSOA (60% female). Descriptive analyses were performed, and values are displayed as means and standard deviations. For subgroup analyses non-parametric tests were used. Results Overall mean age was 60 years (±12 years), and 69% of the patients were female. The mean disease duration was 16±13 years and patients generally showed a good functional status as quantified by the Health Assessment Questionnaire (HAQ mean: 1.0±0.8). While osteoporosis and osteopenia were present in 16% and 38%, respectively, osteoporotic fractures were found in 33% of all patients. However, the family history for osteoporosis was positive in 20% of the patients. The prevalence of osteopenia and osteoporosis was higher in PSO compared to PSOA patients (70% vs. 45%) without reaching statistical significance. 27% of all patients were treated with glucocorticoids: mean daily dose 3±8 mg, mean cumulative dose (GCCD) 10.9 g±20.3 g. No significant difference was seen comparing medians of BMD in patients with a GCCD >10 g versus a GCCD Conclusions In our patient cohort, the GCCD does not have a measurable impact on the BMD. Additionally, according to current literature the prevalence of osteoporosis seems to be in the same range as in the normal population.1 Keeping in mind the (still) small number of patients, neither smoking nor Vit D deficiency could be identified as possible risk factors for low BMD, but further investigations are necessary to corroborate these observations. Reference [1] Hadji, P., et al., The epidemiology of osteoporosis–Bone Evaluation Study (BEST): an analysis of routine health insurance data. Dtsch Arztebl Int, 2013. 110(4): p. 52–7. Disclosure of Interest D. Freier Grant/research support from:. Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, K. Zeiner Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, R. Biesen Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, E. Wiebe Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, T. Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, S. Hermann Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, F. Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche

Background Scientific progress and better disease awareness constantly lead to increasing patient numbers in rheumatology which requires optimization of patient care. Objectives The aim of this study was to evaluate and to optimize the procedures of patient care in an university-based outpatient rheumatology setting in Berlin, Germany. Methods One hundred patients with rheumatoid arthritis (80 women, 20 men, mean age 61.2 years, mean disease duration 12.9 years) were independently assessed both by a rheumatologist and via patient-reported self-assessment questionnaires. Current follow-up interval (usually 3 months), patient9s perspective on follow-up intervals, signs of disease activity as well as individual patient concerns were recorded. Satisfaction with follow-up intervals was grouped into three categories: too early, just right/optimal, too late. Results Based on the physicians perspective, 46 patients presented at the optimal time point, 51 too early, and three too late. The patients reported the category “just right” in 82 cases, too early follow-up in 10 cases and too late in 8 cases. Of note, 51% (42 individuals) of all patients with self-reported satisfactory follow-up interval were judged to visit the out-patient department too early by the expert rheumatologist. When taking into account the follow-up interval and optimal satisfactory levels, 62% of patients were concluded to visit the department too early in those revisited after 3–4 months (n=65), and in 12% of those who were seen again after 5–6 months (n=17). 82% of patients in the latter group were judged to revisit just right by the physician. Conclusions There was a high proportion of overlap in the views on the satisfaction with follow-up intervals between physicians and patients. Especially in patients who were seen every 3–4 months, a high proportion was deemed to could have come later to the out-patient care unit from a purely medical point of view. Here we see a way to stretch the interval to 5–6 months without risking a long-term deterioration in patient care. However, this measure should be flanked by patient education and good collaboration with the general practitioners. Acknowledgements We thank AbbVie for financial support in the development of measures to optimize out-patient management in patients with rheumatoid arthritis. The sponsor did not influence the scientific results. Disclosure of Interest None declared

ObjectiveRheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. We investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints.MethodsCD14+ cells from BM and peripheral blood (PB) of patients with RA and osteoarthritis (OA) were profiled with GeneChip microarrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilisation. Cytometric profiling determined monocyte subsets of CD14++CD16−, CD14++CD16+ and CD14+CD16+ cells in BM, PB and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum.ResultsInvestigation of genes differentially expressed between RA and OA monocytes with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+monocytes in RA-PB. Patterns associated with tumor necrosis factor/lipopolysaccharide (TNF/LPS) stimulation were weak and more pronounced in RA-PB than RA-BM. Cytometric phenotyping of cells in BM, blood and SF disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+monocytes in RA-PB. Monocyte activation in SF was characterised by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P.ConclusionPatterns of less mature and less differentiated RA-BM and RA-PB monocytes suggest increased turnover with accelerated monocytopoiesis, BM egress and migration into inflamed joints. Predominant activation in the joint indicates the action of local and primary stimuli, which may also promote adaptive immune triggering through monocytes, potentially leading to new diagnostic and therapeutic strategies.

Background Targeting molecules involved in monocyte activation is an important treatment strategy for RA. In this study we aimed to determine monocyte maturation and activation from bone marrow (BM) via blood into synovial fluid (SF) by investigating monocytes transcriptomes and by cytometric profiling of classical (CD14++CD16-), intermediated (CD14++CD16+) and non-classical (CD14+CD16+) monocytes. Materials and methods CD14+ cells from BM and blood of RA and osteoarthritis (OA) patients were profiled with Affymetrix microarrays. A detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and egress from BM induced by G-CSF (granulocyte colony-stimulating factor). Cytometric profiling of CD14, CD16, HLA-DR and CD163 expression were used to determine monocyte subsets and to follow their activation and differentiation in BM, blood and SF. Results Transcriptomes of RA-BM monocytes exhibited i) pronounce gene pattern of early myeloid precursors from BM and ii) weak gene pattern of late myeloid precursors from BM. Transcriptomes of RA blood monocytes demonstrated i) pattern of late myeloid precursors from BM and ii) reduced pattern of terminally differentiated CD14+CD16+ monocytes from blood. Cytometric profiling of BM, blood and SF monocytes in RA and OA showed that all three body compartments have their own distribution of monocyte subsets. BM was characterised with classical and intermediate subsets and both subsets showed decreased CD16 expression in RA when compared to OA. As expected, blood was characterised with three subsets, and RA blood showed decreased CD14 and HLA-DR expression on classical monocytes and reduced frequency of non-classical subset. In RA-SF, classical monocytes were absent, intermediate were most dominant and cell-phenotype with low CD16 expression but similar to non-classical monocytes was related to macrophages. Cell frequency of intermediate subset in SF positively correlated with inflammation (ESR; R>0.85) and showed the highest expression of HLA-DR, CD14, CD163. Conclusions Monocyte turnover is increased in RA and characterised with accelerated monocytopoiesis, faster BM egress and migration into inflamed joints. Permanent monocyte activation in the joint and their role in linking innate and adaptive immunity, which is targeted by biologics, emphasises their high diagnostic value and relevance for therapeutic stratification.

To investigate the diagnostic value of single-source dual-energy computed tomography (SDECT) in gouty arthritis and to compare its capability to detect urate depositions with digital radiography (DR) and conventional computed tomography (CT).Forty-four patients who underwent SDECT volume scans of the feet for suspected gouty arthritis were retrospectively analyzed. SDECT, CT (both n=44) and DR (n=36) were scored by three blinded readers for presence of osteoarthritis, erosions, and tophi. A diagnosis was made for each imaging modality. Results were compared to the clinical diagnosis using the American College of Rheumatology (ACR) classification criteria.The patient population was divided into a gout (n=21) and control (n=23) group based on final clinical diagnosis. Osteoarthritis was evident in 15 joints using CT and 30 joints using DR (p=0.165). There were 134 erosions detected by CT compared to 38 erosions detected by DR (p0.001). In total 119 tophi were detected by SDECT, compared to 85 tophi by CT (p=0.182) and 25 tophi by DR (p0.001). SDECT had best diagnostic value for diagnosis of gout compared to DR and conventional CT (sensitivity and specificity for SDECT: 71.4% and 95.7%, CT: 71.4% and 91.3% and DR: 44.4% and 83.3%, respectively). For all three readers, Cohen's kappa for DR and conventional CT were substantial for all scoring items and ranged from 0.75 to 0.77 and 0.72-0.76, respectively. For SDECT Cohen's kappa was good to almost perfect with 0.77-0.84.SDECT is capable to detect uric acid depositions with good sensitivity and high specificity in feet, therefore diagnostic confidence is improved. Using SDECT, inter-reader variance can be markedly reduced for the detection of gouty tophi.

Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb-pathway components is a frequent event in cancer. In concert with the inactivation of cell death pathways, such events not only contribute to tumor development but also determine the intrinsic and acquired resistance to cancer therapy and, ultimately, disease prognosis. We previously observed that the cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog Bax are positive prognostic factors and identify patients with good prognosis in esophageal squamous cell carcinoma (SCC). In the present study, we therefore extend our analysis to additional genes controlling the G(1) restriction point and apoptosis, respectively. This retrospective analysis was performed in a cohort of 53 patients undergoing surgery for esophageal SCC with curative intent, i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb, p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were associated individually with shorter overall survival, while Bcl-2 expression and p53 mutation were not of prognostic relevance. The longest survival was observed in a subgroup of patients whose tumors bore a combination of favorite genotypes, i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein expression. These results show that multigene analyses based on limited sets of functionally linked genes reliably identify patients with good vs. poor prognosis.

Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p < 0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p = 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/BAX pathway (i.e., BAX low/p53 mutated; p = 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.

The purpose of our study was to determine the expression of the pro-apoptotic BAX protein in relation to the mutational status of BAX and p53 (as transcriptional activator of the BAX gene) in benign and malignant thyroid tissue. In 47 patients with thyroid tumours (14 follicular and 3 papillary carcinomas, 14 adenomas and 16 goitres), the DNA was screened for mutations of BAX (exon 1–6) and p53 (exon 5–8) by single-strand conformation polymorphism polymerase chain reaction (SSCP-PCR). Furthermore, the protein expression of BAX, p53 and p21 (which is also increased transcriptionally by p53) was investigated by immunohistochemistry. Surprisingly, we observed elevated BAX levels in patients with thyroid carcinomas compared with patients with adenomas (unpaired t-test: p

Background and objectives Flow cytometry offers quantification of multidimensional characteristics at single cell level for millions of cells. Multiplex flow cytometry or mass cytometry enable to screen for dozens of antigens on a single cell. Conventional analysis of such data requires user defined gating and is time consuming. Using the new bioinformatics tools immunoClust for automated and user-independent analysis, we investigated the complexity of phenotypic changes of immune cells upon migration from peripheral blood (PB) to synovial fluid (SF) in rheumatoid arthritis (RA). Materials and methods Seven paired samples of PB and SF from RA patients were stained in 10 different antibody cocktails and data investigated by the newly developed immunoClust pipeline for sample specific populations and differences between PB and SF. Population clustering and comparative meta-clustering assume finite mixture models and use Expectation Maximisation (EM)-iterations with integrated classification likelihood (ICL) criterion to stabilise the number of reasonable clusters. For meta-clustering, a probability measure on Gaussian distributions was invented, which is based on the Bhattacharyya Coefficients. Meta-clusters were manually annotated and classified. The clustering tools of immunoClust are available as open source R-package in Bioconductor. Results Automated clustering with 46 different surface markers detected all major leukocyte subsets and several activation markers in PB and SF samples including neutrophils, eosinophils, T-cells and sub-populations, monocytes, B-cells, NK-cells and dendritic cells. The comparison revealed about 10 highly significant changes per staining cocktail. For example the percentage of monocytes/macrophages was doubled in SF and dominated by CD16+ cells, the frequencies of effector/memory subpopulations of lymphocytes were increased and naive T-cells and B-cells were almost completely absent. In addition several unexpected populations like CCR7+ monocytes were found in SF only. Conclusion In conclusion, the results give a reasonable starting point to face the next field of research for marker detection and prediction analysis. The data will be further exploited for changes in cell activation and differentiation in SF in order to screen for these populations also in PB. This approach is not only applicable to fluorescence-based flow data but could be also used for multi-parametric data sets generated by mass spectrometry-based cytometry (CyTOF).

To test the hypothesis that microanatomical differences in joint disease localisation could be exploited using high-resolution MRI to better differentiate among rheumatoid arthritis (RA), spondyloarthritis/psoriatic arthritis (SpA/PsA) and osteoarthritis (OA) in clinical practice. Sixty-nine patients with suspected inflammatory joint disease of the hand or feet underwent high-resolution MRI using a small loop coil. Images were scored blinded to the clinical status. Various joint changes like periostitis, osteitis, erosions, enthesitis and synovitis were recorded. The image-based diagnosis was compared with the clinical diagnosis. In 59.4 % of the patients the clinical diagnosis was confirmed on image analysis. This was high for OA (80 %), moderately good for RA (67 %) but only 50 % for SpA/PsA. The major difficulty was to distinguish OA from SpA/PsA where common imaging findings are evident including periostitis (SpA/PsA 45 %, OA 40 % compared with RA 0 %; P = 0.015). Likewise, osteitis was frequently detected in SpA/PsA (79 %) and OA (80 %) and less frequently in RA (42 %) (P = 0.014). Characterisation of inflammatory disorders of small joints merely using high-resolution MRI remains challenging especially in the differentiation between OA and PsA. These findings are likely explained by common microanatomical similarities in disease expression rather than limitations of imaging techniques. • High-resolution MRI is increasingly used to investigate joint disease. • Osteitis and periostitis occur in psoriatic and osteoarthritis (but not rheumatoid arthritis). • In severely affected patients the amount of synovitis and erosions is similar.

Background In addition to joint swelling and tenderness, patients with rheumatoid arthritis (RA) commonly experience morning symptoms of joint stiffness associated with pain that result in impaired function causing morbidity and productivity loss with early disease as well as those with low disease activity or remission1. However, the degree of morning stiffness has never been described. Objectives Although RA patients recognize morning stiffness as being one of the four most significant symptoms to manage, validated morning stiffness patient-reported outcome (PRO) measures are lacking. Therefore, we have developed an approach to objectively quantify finger joint stiffness. The device has been approved by the ethical committee for the use in patients, and has also already obtained a national technical certification. We here present the first results of an ongoing study with this device. Methods So far, nine female postmenopausal RA patients affected by morning stiffness of at least one hour agreed to participate in this study and underwent repetitive measurements of evening and on following morning cycle. These measurements quantified the passive resistance of an affected MCP joint against an externally applied torque while the finger was fixed in the device and passively moved from a completely extended position (referred to as 0°) to a flexed position of 60°. Measurement related sensors and advanced analysis algorithms for the investigation of resulting hysteresis curves enabled both the stiffness and dissipated energy to be evaluated at definite flexion-extension angles. A one-way ANOVA was then applied to test for differences in both parameters between repetitive evening and morning measurements. Results The stiffness of the MCP joint (given in Nm/°) showed highest absolute values at extreme positions, i.e. at 0° and 60°, while lower values were detected at angles in between (Figure 1). At all flexion angles except 0°, stiffness was – as expected – always more pronounced in the morning (red bars) compared with evening measurements (blue bars). The difference found at 40° was statistically significant (p=0.038). Similar results (not shown) were obtained for dissipated energy with a significantly higher value in the morning than in the evening at a flexion angle of 50° (p=0.047). Conclusions Even though the number of patients examined was low and the individual variation of absolute values between subjects is (known to be) considerable, our findings indicate that our approach is capable to differentiate stiffness and dissipated energy in the morning from that measured in the evening. The quantification of these parameters offers for the first time an option for objective evaluation the possibility to objectively evaluate and quantify this important patient-reported outcome in RA. Furthermore, such biomechanical assessments are also very likely able to quantify treatment effects on morning stiffness in the future. References Da Silva, JAP et al.: Impact of impaired morning function on the lives and well-being of patients with rheumatoid arthritis. Scand J Rheumatol. Vol. 125 (2011), pp. 6-11. Acknowledgements This study was funded by Horizon Pharma, USA. Disclosure of Interest H. Boeth: None declared, G. Duda: None declared, D. Hinzmann: None declared, S. Hermann: None declared, W. Taylor: None declared, R. Ehrig: None declared, T. Witaschek: None declared, F. Buttgereit Grant/research support from: Dr. Buttgereit received consultancy fees, honoraria and travel expenses from Merck Serono, Horizon Pharma (formerly Nitec Pharma) and Mundipharma International Ltd, and grant support from Merck Serono and Horizon Pharma

In follicular lymphoma (FL) and mantle cell lymphoma (MCL) the monoclonal antibody rituximab may improve the prognosis when combined with chemotherapy. This was investigated in a prospective randomized study in patients with relapsed disease. A total of 147 patients were randomized to receive 4 courses of chemotherapy with 25 mg/m2 fludarabine on days 1 to 3, 200 mg/m2 cyclophosphamide on days 1 to 3, and 8 mg/m2 mitoxantrone on day 1 (FCM), alone or combined with rituximab (375 mg/m2; R-FCM). Of 128 evaluable patients, 62 were randomized for FCM and 66 for R-FCM. RFCM revealed an overall response rate of 79% (33% complete remission [CR], 45% partial remission [PR]) as compared with 58% for FCM alone (13% CR, 45% PR; P .01), with similar results in a subgroup analysis of FL (94% vs 70%) and MCL (58% vs 46%). In the total group, the R-FCMarmwassignificantlysuperiorconcerning progression-free survival (PFS; P .0381) and overall survival (OS; P .0030). In FL PFS was significantly longer in the R-FCM arm (P .0139) whereas in MCL a significantly longer OS was observed (P .0042). There were no differences in clinically relevant side effects in both study arms. Hence, the addition of rituximab to FCM chemotherapy significantly improves the outcome of relapsed or refractory FLand MCL. (Blood. 2004;104:3064-3071)

Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb-pathway components is a frequent event in cancer. In concert with the inactivation of cell death pathways, such events not only contribute to tumor development but also determine the intrinsic and acquired resistance to cancer therapy and, ultimately, disease prognosis. We previously observed that the cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog Bax are positive prognostic factors and identify patients with good prognosis in esophageal squamous cell carcinoma (SCC). In the present study, we therefore extend our analysis to additional genes controlling the G(1) restriction point and apoptosis, respectively. This retrospective analysis was performed in a cohort of 53 patients undergoing surgery for esophageal SCC with curative intent, i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb, p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were associated individually with shorter overall survival, while Bcl-2 expression and p53 mutation were not of prognostic relevance. The longest survival was observed in a subgroup of patients whose tumors bore a combination of favorite genotypes, i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein expression. These results show that multigene analyses based on limited sets of functionally linked genes reliably identify patients with good vs. poor prognosis.

Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p = 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/BAX pathway (i.e., BAX low/p53 mutated; p = 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.