Klaus Bobacz

Interleukin-1 is essential for systemic inflammatory bone loss

Objectives: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined. Methods: To determine whether TNF directly triggers bone loss or requires IL1, human TNFα mice (hTNFtg) were crossed with mice lacking IL1α and IL1β (IL1−/−hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism. Results: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1−/−hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice. Conclusions: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.

Effect of pulsed electromagnetic fields on proteoglycan biosynthesis of articular cartilage is age dependent

Objective: To investigate the effects of a pulsed electromagnetic field (EMF) on articular cartilage matrix biosynthesis with regard to age and cartilage damage using a matrix depleted cartilage explant model. Methods: Cartilage explants were obtained from metacarpophalangeal joints of calves and adult cows. After depletion of the extracellular matrix by trypsin digestion, samples were maintained in serum-free basal medium with and without the addition of interleukin 1β (IL1β). Half the samples were subjected to an EMF for 24 minutes daily; the other half were left untreated. Undigested and untreated explants served as negative controls. After 7 days, biosynthesis of matrix macromolecules was assessed by [35S]sulphate incorporation and values were normalised to hydroxyproline content. Results: The EMF increased matrix macromolecule synthesis in undigested, untreated explants (p<0.009). In matrix depleted samples the EMF had no stimulatory effect on proteoglycan biosynthesis. IL1β significantly decreased the de novo synthesis of matrix macromolecules (p<0.00004) in young and adult samples, but an EMF partly counteracted this inhibitory effect in cartilage samples from young, but not old animals. Conclusion: EMF promoted matrix macromolecule biosynthesis in intact tissue explants but had no stimulatory effect on damaged articular cartilage. The supressive effects of IL1β were partially counteracted by EMF exposure, exclusively in cartilage derived from young animals. An EMF has age dependent chondroprotective but not structure modifying properties when cartilage integrity is compromised.

OP0095 Randomized, Placebo-Controlled Trial To Evaluate Clinical Efficacy and Structure Modifying Properties of Subcutaneous Etanercept (ETN) in Patients with Erosive Inflammatory Hand Osteoarthritis (OA)

Background Erosive OA involves interphalangeal joints (IPJs), resulting in a high disease burden, for which treatment options are limited. Although it is characterized by joint inflammation, earlier treatment with TNF blockers was equivocal. Objectives To investigate the 1-year efficacy of ETN in erosive OA. Methods In a European multicentre study (NTR 1192) patients were equally randomized to subcutaneous ETN (24 weeks 50 mg weekly, thereafter 25 mg weekly) or placebo. Patients with erosive (≥1 IPJ with radiographic pre(erosive) anatomical phase (“J”/“E”) according to Verbruggen-Veys system) inflammatory (≥1 IPJ with soft swelling/erythema and with positive power Doppler at US) symptomatic (VAS pain >30/100 on NSAID use, flare after NSAID washout) OA were included. VAS pain, hand function (FIHOA), quality of life (SF-36), no. of tender joints and grip strength were assessed after 4, 8, 12, 24, 36 weeks and 1 year. Radiographic progression of IPJs was scored blindly in paired order (baseline, 24 weeks and 1 year) following the quantitative Ghent University Scoring System (GUSS, 0–300 per IPJ). With linear mixed models VAS pain was compared between treatment groups at 24 weeks (primary outcome), and 1 year in intention-to-treat (ITT) analyses. With general estimated equations secondary outcomes were analysed. Adjustments were made for centre, baseline values and patient effects were appropriate. Completers fulfilling the extensive inclusion criteria were included in per-protocol (PP) analyses. Results Of 284 screened patients, 90 (mean age 60 years, 81% women, 96% fulfilled ACR hand OA criteria) were randomized; 22 discontinued the study prematurely. At baseline patient characteristics did not differ between the groups. VAS pain in all patients decreased -24.8 mm (95%CI -29.2;-20.5 (P<0.001)) at 24 weeks. In ITT differences in pain between the groups were in favour of ETN, but did not reach statistical significance. However, in PP the difference reached statistical significance (table). No differences were seen on secondary clinical outcomes. The PP analysis of GUSS showed a mean difference in favour of ETN (table), indicating more remodelling in the ETN group. Additional analyses showed an interaction between soft swelling/erythema and ETN treatment on GUSS, resulting in a statistical significant (P<0.05) mean difference between ETN and placebo groups. More patients dropped out on placebo than on ETN (6 vs. 3) due to inefficacy, whereas more on ETN than on placebo (6 vs. 1) due to adverse effects. Conclusions In erosive OA ETN was not superior over placebo on VAS pain at 24 weeks. However in the symptomatic and inflammatory patients completing the study ETN was superior over placebo both on pain and structural damage assessed by GUSS; ETN was especially effective in joints with signs of inflammation. Acknowledgement Pfizer for supply of study medication and research grant. Disclosure of Interest None declared

Impairment of chondrocyte biosynthetic activity by exposure to 3-tesla high-field magnetic resonance imaging is temporary

The influence of magnetic resonance imaging (MRI) devices at high field strengths on living tissues is unknown. We investigated the effects of a 3-tesla electromagnetic field (EMF) on the biosynthetic activity of bovine articular cartilage. Bovine articular cartilage was obtained from juvenile and adult animals. Whole joints or cartilage explants were subjected to a pulsed 3-tesla EMF; controls were left unexposed. Synthesis of sulfated glycosaminoglycans (sGAGs) was measured by using [35S]sulfate incorporation; mRNA encoding the cartilage markers aggrecan and type II collagen, as well as IL-1β, were analyzed by RT–PCR. Furthermore, effects of the 3-tesla EMF were determined over the course of time directly after exposure (day 0) and at days 3 and 6. In addition, the influence of a 1.5-tesla EMF on cartilage sGAG synthesis was evaluated. Chondrocyte cell death was assessed by staining with Annexin V and TdT-mediated dUTP nick end labelling (TUNEL). Exposure to the EMF resulted in a significant decrease in cartilage macromolecule synthesis. Gene expression of both aggrecan and IL-1β, but not of collagen type II, was reduced in comparison with controls. Staining with Annexin V and TUNEL revealed no evidence of cell death. Interestingly, chondrocytes regained their biosynthetic activity within 3 days after exposure, as shown by proteoglycan synthesis rate and mRNA expression levels. Cartilage samples exposed to a 1.5-tesla EMF remained unaffected. Although MRI devices with a field strength of more than 1.5 T provide a better signal-to-noise ratio and thereby higher spatial resolution, their high field strength impairs the biosynthetic activity of articular chondrocytes in vitro. Although this decrease in biosynthetic activity seems to be transient, articular cartilage exposed to high-energy EMF may become vulnerable to damage.

Histopathological correlation supports the use of x-rays in the diagnosis of hand osteoarthritis

Objective To correlate histopathological and radiographic features of distal and proximal interphalangeal (DIP and PIP) joints in order to test whether the use of an x-ray examination would be beneficial to the classification/diagnosis process of hand osteoarthritis (OA). Methods DIP and PIP joints were obtained from post mortem specimens (n=40). Plain x-rays of the DIP and PIP joints were taken and radiographic OA was determined by the Kellgren and Lawrence classification. Individual radiographic features were scored according to the method described by Altman. Joint samples were prepared for histological analysis; cartilage damage was graded according to the Mankin scoring system. Spearmans correlation was applied to examine the relationship between histological and radiographical changes. Differences between groups (bony swelling vs no bony swelling) were determined by Student t test. Results A highly significant correlation was found between histological (Mankin score) and radiographic (Kellgren/Lawrence score) changes in the investigated DIP (rs=0.87, p<0.0001) and PIP (rs=0.79, p<0.0001) joints. A subgroup of patients (37.5% for DIP and 18.8% for PIP joints) showed advanced radiographic changes (Kellgren/Lawrence score ≥2) in joints without clinical bony swelling. Histologically, the mean Mankin scores accounted for 11±1.66 for DIP and 9.67±2.4 for PIP joints. Conclusion On the basis of histopathological changes of DIP and PIP joints, this investigation demonstrates the validity of x-ray examinations and supports the use of plain radiography in the diagnosis of hand OA and in the classification of hand OA in clinical trials.

Interphalangeal Osteoarthritis Radiographic Simplified (iOARS) score: a radiographic method to detect osteoarthritis of the interphalangeal finger joints based on its histopathological alterations

Objective To develop a radiographic score for assessment of hand osteoarthritis (OA) that is based on histopathological alterations of the distal (DIP) and proximal (PIP) interphalangeal joints. Methods DIP and PIP joints were obtained from corpses (n=40). Plain radiographies of these joints were taken. Joint samples were prepared for histological analysis; cartilage damage was graded according to the Mankin scoring system. A 2×2 Fishers exact test was applied to define those radiographic features most likely to be associated with histological alterations. Receiver operating characteristic curves were analysed to determine radiographic thresholds. Intraclass correlation coefficients (ICC) estimated intra- and inter-reader variability. Spearmans correlation was applied to examine the relationship between our score and histopathological changes. Differences between groups were determined by a Students t test. Results The Interphalangeal Osteoarthritis Radiographic Simplified (iOARS) score is presented. The score is based on histopathological changes of DIP and PIP joints and follows a simple dichotomy whether OA is present or not. The iOARS score relies on three equally ranked radiographic features (osteophytes, joint space narrowing and subchondral sclerosis). For both DIP and PIP joints, the presence of one x-ray features reflects interphalangeal OA. Sensitivity and specificity for DIP joints were 92.3% and 90.9%, respectively, and 75% and 100% for PIP joints. All readers were able to reproduce their own readings in DIP and PIP joints after 4 weeks. The overall agreement between the three readers was good; ICCs ranged from 0.945 to 0.586. Additionally, outcomes of the iOARS score in a hand OA cohort revealed a higher prevalence of interphalangeal joint OA compared with the Kellgren and Lawrence score. Conclusions The iOARS score is uniquely based on histopathological alterations of the interphalangeal joints in order to reliably determine OA of the DIP and PIP joints radiographically. Its high specificity and sensitivity together with the dichotomous approach renders the iOARS score reliable, fast to perform and easy to apply. This tool may not only be valuable in daily clinical practice but also in clinical and epidemiological trials.

Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial

Objective Hand osteoarthritis is a prevalent disease with limited treatment options. Since joint inflammation is often present, we investigated tumour necrosis factor (TNF) as treatment target in patients with proven joint inflammation in a proof-of-concept study. Methods This 1-year, double-blind, randomised, multicentre trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand osteoarthritis. Patients flaring after non-steroidal anti-inflammatory drug washout were randomised to etanercept (24 weeks 50 mg/week, thereafter 25  mg/week) or placebo. The primary outcome was Visual Analogue Scale (VAS) pain at 24 weeks. Secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n=54) and MRIs (n=20)). Results Of 90 patients randomised to etanercept (n=45) or placebo (n=45), respectively, 12 and 10 discontinued prematurely. More patients on placebo discontinued due to inefficacy (6 vs 3), but fewer due to adverse effects (1 vs 6). The mean between-group difference (MD) in VAS pain was not statistically significantly different (−5.7 (95% CI −15.9 to 4.5), p=0.27 at 24 weeks; − 8.5 (95% CI −18.6 to 1.6), p=0.10 at 1  year; favouring etanercept). In prespecified per-protocol analyses of completers with pain and inflammation at baseline (n=61), MD was −11.8 (95% CI −23.0 to −0.5) (p=0.04) at 1  year. Etanercept-treated joints showed more radiographic remodelling (delta GUSS: MD 2.9 (95% CI 0.5 to 5.4), p=0.02) and less MRI bone marrow lesions (MD −0.22 (95% CI −0.35 to −0.09), p = 0.001); this was more pronounced in joints with baseline inflammation. Conclusion Anti-TNF did not relieve pain effectively after 24 weeks in erosive osteoarthritis. Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies to confirm this are warranted.

The Case | Myeloid bodies in the kidney biopsy of a patient with systemic lupus erythematosus

The Case | Myeloid bodies in the kidney biopsy of a patient with systemic lupus erythematosus Marija Bojic, Nicolas Kozakowski, Manuel Bécède, Andreas Kerschbaumer and Klaus Bobacz Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria; Department of Pathology, Medical University of Vienna, Vienna, Austria; and Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria