F.P. Kroon

Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis

Objectives The aim was to compare continuous and on-demand NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels, ESR, ASDAS-levels or BASDAI-levels in comparison to patients with normal levels. Methods Post-hoc analyses were performed in a randomized trial comparing continuous and on-demand NSAID treatment. Relevant high/elevated subgroups were created based on time-averaged (ta) CRP (>5mg/L), ta-ESR (>12mm/hr), ta-BASDAI (>4), ta-ASDAS-CRP (>2.1) and ta-ASDAS-ESR (>2.1). Subgroups were further split according to NSAID-use (continuous vs. on-demand). Radiological progression was presented in probability plots. Statistical interactions were tested using multiple and logistic regression analysis. Differences in radiological progression were analysed using the Chi-square and Mann-Whitney U test. Results 150 participants randomized to either the continuous-treatment group (n=76), or the on-demand group (n=74) had complete radiographs and were included. The effect of slowing radiological progression with continuous NSAID therapy was more pronounced in patients with elevated ta-CRP-levels, elevated ta-ESR, high ta-ASDAS-CRP or high ta-ASDAS-ESR versus patients with low/normal values. No such effect was found for participants with high vs. low BASDAI. Also, in participants with elevated ta-ESR (irrespective of treatment), there appeared to be a higher rate of structural progression than in participants with normal ta-ESR. Regression analyses showed that continuous NSAID treatment neutralizes the negative effect of inflammation (high ta-ESR). Conclusions Patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs. Continuous NSAID-therapy in patients with elevated acute phase reactants may lead to an improved benefit-risk-ratio of these drugs.

Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis.

M.G.J. de Boer, F.P. Kroon, S. le Cessie, J.W. de Fijter, J.T. van Dissel. Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis.
Transpl Infect Dis 2011: 13: 559–569. All rights reserved

Two‐Year Results of a Randomized Placebo‐Controlled Trial of Vertebroplasty for Acute Osteoporotic Vertebral Fractures

We previously reported the results of a randomized controlled trial that found no benefit of vertebroplasty over a sham procedure for acute osteoporotic vertebral fractures up to 6 months. We report here the 12‐month and 24‐month clinical outcomes of this trial. Eligible participants (n = 78) were randomly assigned to receive either vertebroplasty (n = 38) or a sham procedure (n = 40). Randomization was stratified by treatment center, sex, and symptom duration (<6 weeks or ≥6 weeks). Participants, investigators (except the treating radiologists), and outcome assessors were blinded to group assignments. Enrolment occurred between April 2004 and October 2008 with follow‐up completed October 2010. The primary outcome was overall pain measured on a scale of 0 (no pain) to 10 (maximal imaginable pain). Secondary outcomes included pain at rest and at night, disability, quality of life, perceived recovery, and adverse events, including incident clinically apparent vertebral fractures. At 12 and 24 months, complete data were available for 67 (86%) and 57 (73%) participants, respectively. At 12 months participants in the active group improved by 2.4 ± 2.7 (mean ± SD) units in overall pain compared with 1.9 ± 2.8 units in the sham group, adjusted between‐group mean difference (MD) 0.3 (95% confidence interval [CI], –0.9 to 1.5), whereas at 24 months participants in the active group had improved by 3.0 ± 3.1 units compared with 1.9 ± 3.0 units in the sham group, MD 1.1 (95% CI, –0.3 to 2.4). No significant between‐group differences were observed for any of the secondary efficacy outcomes at 12 or 24 months. There were no between‐group differences in incident clinical vertebral fractures up to 24 months (active: n = 14, sham: n = 13), although the study had inadequate power for this outcome. These results provide further evidence that the use of this treatment in routine care is unsupported.

Preliminary definitions of ‘flare’ in axial spondyloarthritis, based on pain, BASDAI and ASDAS-CRP: an ASAS initiative

Introduction Flares may be used as outcomes in axial spondyloarthritis (axSpA) trials or observational studies. The objective was to develop a definition for ‘flare’ (or worsening) in axSpA, based on validated composite indices, to be used in the context of clinical trial design. Methods (1) Systematic literature review of definitions of ‘flare’ in published randomised controlled trials in axSpA. (2) Vignette exercise: 140 scenarios were constructed for a typical patient with axSpA seen at two consecutive visits. Each scenario included a change in one of the following outcomes: pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI plus C-reactive protein (CRP) or Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP. Each Assessment of Spondyloarthritis (ASAS) expert determined if every scenario from a random sample of 46 scenarios was considered a flare (yes/no). Receiver-operating characteristic (ROC) analyses were applied to derive optimal cut-off values. (3) ASAS consensus was reached. Results (1) The literature review yielded 38 studies using some definition of ‘flare’, with 27 different definitions indicating important heterogeneity. The most frequent definitions were based on BASDAI changes or pain changes. (2) 121 ASAS experts completed 4999 flare assessments. The areas under the ROC curves were high (range: 0.88–0.89). Preliminary cut-offs for pain (N=3), BASDAI (N=5) and ASDAS-CRP (N=4) were chosen, with a range of sensitivity 0.60–0.99 and range of specificity 0.40–0.94 against the experts opinions. Conclusions This data-driven ASAS consensus process has led to 12 preliminary draft definitions of ‘flare’ in axSpA, based on widely used indices. These preliminary definitions will need validation in real patient data.

Development and Reliability of the OMERACT Thumb Base Osteoarthritis Magnetic Resonance Imaging Scoring System

Objective. To develop the Outcome Measures in Rheumatology (OMERACT) thumb base osteoarthritis (OA) magnetic resonance imaging (MRI) scoring system (TOMS) for the assessment of inflammatory and structural abnormalities in this hand OA subset, and test its cross-sectional reliability. Methods. Included features and their scaling were agreed upon by members of the OMERACT MRI Task Force using the Hand OA MRI scoring system as a template. A reliability exercise was performed in which 3 readers participated, using a preliminary atlas with examples to facilitate reading. Each reader independently scored a set of 20 MRI (coronal and axial T1- and T2-weighted fat-suppressed images, of which 5 included T1-weighted fat-suppressed post-Gadolinium images). Intra- and inter-reader reliability were assessed using ICC, percentage exact agreement (PEA), and percentage close agreement (PCA). Results. The TOMS assessed the first carpometacarpal (CMC-1) and scaphotrapeziotrapezoid (STT) joints for synovitis, subchondral bone defects (including erosions, cysts, and bone attrition), osteophytes, cartilage, and bone marrow lesions on a 0–3 scale (normal to severe). Subluxation was evaluated only in the CMC-1 joint (absent/present). Reliability of scoring for both joints was comparable. Interreader ICC were good for all features (0.77–0.99 and 0.74–0.96 for CMC-1 and STT joints, respectively). Intrareader reliability analyses gave similar results. PCA was ≥ 65% for all features. PEA was low to moderate, with better performance for subchondral bone defects, subluxation, and bone marrow lesions. Conclusion. A thumb base OA MRI scoring system has been developed. The OMERACT TOMS demonstrated good intrareader and interreader reliability. Longitudinal studies are warranted to investigate reliability of change scores and responsiveness.

Nonsteroidal Antiinflammatory Drugs for Axial Spondyloarthritis: A Cochrane Review

Objective. To determine the benefits and harms of nonsteroidal antiinflammatory drugs (NSAID) in axial spondyloarthritis (axSpA). Methods. Systematic review using Cochrane Collaboration methodology. Inclusion criteria: randomized controlled trials (RCT) and quasi-RCT (to June 2014), investigating NSAID versus any control for axSpA, and observational studies of longterm effects (≥ 6 mos) of NSAID on radiographic progression or adverse events. Main outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, radiographic progression, number of withdrawals because of adverse events, and number of serious adverse events. Risk of bias was assessed. Results. Thirty-five RCT, 2 quasi-RCT, and 2 cohort studies were included. Twenty-nine RCT and 2 quasi-RCT (n = 4356) were included in pooled analyses [traditional NSAID vs placebo (n = 5), cyclooxygenase-2 (COX-2) vs placebo (n = 3), COX-2 vs traditional NSAID (n = 4), NSAID vs NSAID (n = 24), naproxen vs other NSAID (n = 3), and low- vs high-dose NSAID (n = 5)]. Compared with placebo, both traditional and COX-2 NSAID were consistently more efficacious at 6 weeks and equally safe after 12 weeks. No significant differences in benefits or harms between the 2 NSAID classes and no important differences in benefits or withdrawals because of adverse events between different NSAID were found, especially if studies with high risk of bias were excluded. Single studies suggest NSAID may retard radiographic progression, especially by continuous rather than on-demand NSAID use. Conclusion. High-quality evidence indicates that both traditional and COX-2 NSAID are efficacious for treating axSpA, and harms are not different from placebo in the short term. Various NSAID are equally effective.

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

Do Comorbidities Play a Role in Hand Osteoarthritis Disease Burden? Data from the Hand Osteoarthritis in Secondary Care Cohort

Objective. Because the association and its clinical relevance between comorbidities and primary hand osteoarthritis (OA) disease burden is unclear, we studied this in patients with hand OA from our Hand OSTeoArthritis in Secondary care (HOSTAS) cohort. Methods. Cross-sectional data from the HOSTAS study were used, including consecutive patients with primary hand OA. Nineteen comorbidities were assessed: 18 self-reported (modified Charlson index and osteoporosis) and obesity (body mass index ≥ 30 kg/m2). Mean differences were estimated between patients with versus without comorbidities, adjusted for age and sex: for general disease burden [health-related quality of life (HRQOL), Medical Outcomes Study Short Form-36 physical component scale (0–100)] and disease-specific burden [self-reported hand function (0–36), pain (0–20; Australian/Canadian Hand OA Index), and tender joint count (TJC, 0–30)]. Differences above a minimal clinically important improvement/difference were considered clinically relevant. Results. The study included 538 patients (mean age 61 yrs, 86% women, 88% fulfilled American College of Rheumatology classification criteria). Mean (SD) HRQOL, function, pain, and TJC were 44.7 (8), 15.6 (9), 9.3 (4), and 4.8 (5), respectively. Any comorbidity was present in 54% (287/531) of patients and this was unfavorable [adjusted mean difference presence/absence any comorbidity (95% CI): HRQOL −4.4 (−5.8 to −3.0), function 1.9 (0.4–3.3), pain 1.4 (0.6–2.1), TJC 1.3 (0.4–2.2)]. Number of comorbidities and both musculoskeletal (e.g., connective tissue disease) and nonmusculoskeletal comorbidities (e.g., pulmonary and cardiovascular disease) were associated with disease burden. Associations with HRQOL and function were clinically relevant. Conclusion. Comorbidities showed clinically relevant associations with disease burden. Therefore, the role of comorbidities in hand OA should be considered when interpreting disease outcomes and in patient management.

OP0168 A phase 2a, placebo-controlled, randomized study of ABT-981, an anti-interleukin-1ALPHA and -1BETA dual variable domain immunoglobulin, to treat erosive hand osteoarthritis (EHOA)

Background No approved OA therapies reduce pain and slow joint damage. Mouse data suggested that inhibiting IL-1α and -1β with ABT-981 would reduce pain and slow structural progression in EHOA. Objectives To test the efficacy and safety of ABT-981 in EHOA. Methods Subjects with HOA per ACR criteria, ≥3 inflamed IP joints (tender, swollen, or both), hand pain ≥6 (scale 0–10), and ≥1 erosive IP joint on X-ray (Verbruggen-Veys) were randomized to placebo (PBO) or ABT-981 200 mg SC every 2 wk for 26 wk. The primary outcome was AUSCAN hand pain at 16 wk. Subjects had radiographs of both hands and MRI of the index hand at baseline and 26 wk. Both radiographs (Verbruggen-Veys, GUSS™, OARSI, Kellgren-Lawrence [KL]) and MRIs (HOAMRIS) were read by 2 independent central readers. A modified intent-to-treat population (ie, randomized and treated) was analyzed. Continuous efficacy endpoints were assessed using ANCOVA models with treatment and country as main factors and baseline measurements as covariates with LOCF imputation for the primary endpoint. Results Of 131 treated subjects (85% women; mean age 66 y), 61/67 randomized to PBO and 49/64 to ABT-981 completed the study; subject characteristics were well matched. AUSCAN pain was not significantly different vs PBO at wk 16 (P=0.39; Table 1, Figure); X-ray data and other endpoints also were not statistically different vs PBO (Table 1). ABT-981 significantly decreased hsCRP, neutrophils, IL-1α, and IL-1β. Immunogenicity had no impact on ABT-981 pharmacokinetics. Besides injection site reactions and neutropenia, ABT-981 was well tolerated and safety was similar vs PBO, with no serious infections (Table 2).Table 1 PBO ABT-981 PBO ABT-981 P 1° Endpoint Baseline, mean±SD LS, mean change±SE at Wk 16 AUSCAN pain (0–50) 39±7 38±6 −10.7±2.4 −9.2±2.3 0.39 2° Endpoints Baseline, mean±SD LS, mean change±SE at Wk 26 AUSCAN function (0–90) 69±15 71±13 −14.3±4.2 −16.4±4.0 0.49 Tender joints (0–30) 12±6 12±7 −4.7±1.2 −5.8±1.2 0.32 Swollen joints (0–30) 6±6 6±5 −1.8±0.8 −2.2±0.9 0.64 X-ray erosive joints (0–16) 2±2* 3±2* 0.26±0.08† 0.18±0.08† 0.33 KL score (0–80) 41±13 46±13 0.13±0.19 0.10±0.19 0.87 OARSI JSN (0–58) 28±10 32±9 0.14±0.19 0.03±0.19 0.51 OARSI osteophytes (0–58) 23±11 26±10 0.25±0.15 0.14±0.16 0.45 HOAMRIS synovitis (sum score; 0–52.5) 11±4 10±4 0.92±0.48 0.85±0.51 0.89 HOAMRIS erosive damage (sum score; 0–105) 18±9 17±10 0.26±0.64 0.10±0.67 0.80 HOAMRIS BML (sum score, 0–105) 7±5 5±4 0.11±0.64 0.44±0.66 0.60 *Verbruggen-Veys, erosive phase (E) + erosive with remodeling (E/R) or†new E or E/R or R.Table 2 PBO (n=67) ABT-981 (n=64) Any AE/serious AE, % 88/3 91/3 Death, % 0 0 Infection/serious infection, % 51/0 41/0 Injection site reaction, % 16 36 Neutropenia by NCI CTCAE grade, n  G2 (1000 to <1500/mm3) 0 9  G3 (500 to <1000/mm3) 0 3  G4 (<500/mm3) 0 0 Conclusions Despite adequate pharmacodynamics results, targeting IL-1 may be ineffective in EHOA, as ABT-981 did not improve outcomes. Acknowledgements AbbVie funded the study (NCT02384538); participated in study design, data collection, analysis, and interpretation and in abstract writing, review, and approval; and funded writing support by M. Theisen of CPS. Disclosure of Interest M. Kloppenburg Grant/research support from: Pfizer, Consultant for: AbbVie, GlaxoSmithKline, Merck, Levicept, C. Peterfy Shareholder of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), Employee of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), Speakers bureau: Amgen, I. Haugen Consultant for: AbbVie, F. Kroon: None declared, S. Chen Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, W. Liu Shareholder of: AbbVie, Employee of: AbbVie, G. Levy Shareholder of: AbbVie, Employee of: AbbVie, R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, F. Berenbaum Consultant for: AbbVie, Pfizer, Regeneron, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB, Employee of: Director of Imaging Rheumatology bv., J. Medema Shareholder of: AbbVie, Employee of: AbbVie, M. Levesque Shareholder of: AbbVie, Employee of: AbbVie

2018 update of the EULAR recommendations for the management of hand osteoarthritis

Since publication of the European League Against Rheumatism (EULAR) recommendations for management of hand osteoarthritis (OA) in 2007 new evidence has emerged. The aim was to update these recommendations. EULAR standardised operating procedures were followed. A systematic literature review was performed, collecting the evidence regarding all non-pharmacological, pharmacological and surgical treatment options for hand OA published to date. Based on the evidence and expert opinion from an international task force of 19 physicians, healthcare professionals and patients from 10 European countries formulated overarching principles and recommendations. Level of evidence, grade of recommendation and level of agreement were allocated to each statement. Five overarching principles and 10 recommendations were agreed on. The overarching principles cover treatment goals, information provision, individualisation of treatment, shared decision-making and the need to consider multidisciplinary and multimodal (non-pharmacological, pharmacological, surgical) treatment approaches. Recommendations 1–3 cover different non-pharmacological treatment options (education, assistive devices, exercises and orthoses). Recommendations 4–8 describe the role of different pharmacological treatments, including topical treatments (preferred over systemic treatments, topical non-steroidal anti-inflammatory drugs (NSAIDs) being first-line choice), oral analgesics (particularly NSAIDs to be considered for symptom relief for a limited duration), chondroitin sulfate (for symptom relief), intra-articular glucocorticoids (generally not recommended, consider for painful interphalangeal OA) and conventional/biological disease-modifying antirheumatic drugs (discouraged). Considerations for surgery are described in recommendation 9. The last recommendation relates to follow-up. The presented EULAR recommendations provide up-to-date guidance on the management of hand OA, based on expert opinion and research evidence.