J.M. van Laar

A Personalized Approach to Biological Therapy Using Prediction of Clinical Response Based on MRP8/14 Serum Complex Levels in Rheumatoid Arthritis Patients

Objectives Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. Methods Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. Results The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. Conclusions Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness.

Long-term outcome is better when a methotrexate-based treatment strategy is combined with 10 mg prednisone daily: follow-up after the second Computer-Assisted Management in Early Rheumatoid Arthritis trial

Objectives In the second Computer-Assisted Management in Early Rheumatoid Arthritis trial, patients had started with methotrexate and 10 mg prednisone (MTX+pred) or placebo (MTX+plac). After the trial, prednisone was tapered and stopped, if possible. The objective was to compare, during the post-trial follow-up between the two former strategy groups, initiation of the first biological disease-modifying antirheumatic drug (bDMARD), radiographic outcome and onset of glucocorticoid (GC)-related comorbidities. Methods Data on prednisone and bDMARD use and onset of GC-related comorbidities were collected retrospectively. Sharp/van der Heijde scoring was performed. Data were analysed using Fisher’s exact and Mann-Whitney U tests. Results Of 218 patients post-trial follow-up data were available. The maximum follow-up time was 11.8 years. Fewer patients initiated a first bDMARD in the former MTX+pred compared with the former MTX+plac strategy group: 31% vs 50%, p=0.003. At the 2 year post-trial follow-up, the median erosion score was significantly lower in the former MTX+pred versus former MTX+plac strategy group: 0 (range 0–0) versus 0 (0–2), p=0.002. No significant differences between the former strategy groups in the onset of GC-related comorbidities during the post-trial follow-up were found. Conclusion Addition of 10 mg prednisone daily to an MTX-based treatment strategy in early rheumatoid arthritis results in a lower initiation rate of a first bDMARD and significantly better radiographic outcomes, yet does not result in more GC-related comorbidities.

A fusion protein of interleukin‐4 and interleukin‐10 protects against blood‐induced cartilage damage in vitro and in vivo

Essentials Targeted treatment for hemophilic arthropathy, still causing significant morbidity, is lacking. This study evaluates the efficacy of a fusion of protein of interleukin(IL)‐4 and IL‐10. In vitro the fusion protein prevents blood‐induced cartilage damage in a dose‐dependent manner. In hemophilic mice, the IL4‐10 fusion protein ameliorates cartilage damage upon joint bleeding.

Knee Joint Distraction Compared to Total Knee Arthroplasty for Treatment of End Stage Osteoarthritis: Simulating Long-Term Outcomes and Cost-Effectiveness.

Objective In end-stage knee osteoarthritis the treatment of choice is total knee arthroplasty (TKA). An alternative treatment is knee joint distraction (KJD), suggested to postpone TKA. Several studies reported significant and prolonged clinical improvement of KJD. To make an appropriate decision regarding the position of this treatment, a cost-effectiveness and cost-utility analysis from healthcare perspective for different age and gender categories was performed. Methods A treatment strategy starting with TKA and a strategy starting with KJD for patients of different age and gender was simulated. To extrapolate outcomes to long-term health and economic outcomes a Markov (Health state) model was used. The number of surgeries, QALYs, and treatment costs per strategy were calculated. Costs-effectiveness is expressed using the cost-effectiveness plane and cost-effectiveness acceptability curves. Results Starting with KJD the number of knee replacing procedures could be reduced, most clearly in the younger age categories; especially revision surgery. This resulted in the KJD strategy being dominant (more effective with cost-savings) in about 80% of simulations (with only inferiority in about 1%) in these age categories when compared to TKA. At a willingness to pay of 20.000 Euro per QALY gained, the probability of starting with KJD to be cost-effective compared to starting with a TKA was already found to be over 75% for all age categories and over 90–95% for the younger age categories. Conclusion A treatment strategy starting with knee joint distraction for knee osteoarthritis has a large potential for being a cost-effective intervention, especially for the relatively young patient.

Gouty arthritis: decision-making following dual-energy CT scan in clinical practice, a retrospective analysis

To establish whether dual-energy CT (DECT) is a diagnostic tool, i.e., associated with initiation or discontinuation of a urate lowering drug (ULD). Secondly, to determine whether DECT results (gout deposition y/n) can be predicted by clinical and laboratory variables. Digital medical records of 147 consecutive patients with clinical suspicion of gout were analyzed retrospectively. Clinical data including medication before and after DECT, lab results, and results from diagnostic joint aspiration and DECT were collected. The relationship between DECT results and clinical and laboratory results was evaluated by univariate regression analyses; predictors showing a p < 0.10 were entered in a multivariate logistic regression model with the DECT result as outcome variable. A backward stepwise technique was applied. After the DECT, 104 of these patients had a clinical diagnosis of gout based on the clinical judgment of the rheumatologist, and in 84 of these patients, the diagnosis was confirmed by demonstration of monosodium urate (MSU) crystals in synovial fluid (SF) or by positive DECT. After DECT, the current ULD was modified in 33 (22.4%) of patients; in 29 of them, ULD was started and in 1 it was intensified. Following DECT, the current ULD was stopped in three patients. In the multivariable regression model, cardiovascular disease (OR 3.07, 95% CI 1.26–7.47), disease duration (OR 1.008, 95% CI 1.001–1.016), frequency of attack (OR 1.23, 95% CI 1.07–1.42), and creatinine clearance (OR 2.03, 95% CI 0.91–1.00) were independently associated with positive DECT results. We found that the DECT result increases the confidence of the prescribers in their decision to initiation or discontinuation of urate lowering therapy regimen in of mono- or oligoarthritis. It may be a useful imaging tool for patients who cannot undergo joint aspiration because of contraindications or with difficult to aspirate joints, or those who refuse joint aspiration. We also suggest the use of DECT in cases where a definitive diagnosis cannot be made from signs, symptoms, and MSU analysis alone.

Lack of a clear disease modifying activity of celecoxib in treatment of end-stage knee osteoarthritis: a rondomized observer blinded clinical trial

Objective: To evaluate the in vivo disease modifying activity of the selective COX-2 inhibitor celecoxib, compared to no-treatment and naproxen, treating end-stage knee osteoarthritis, using detailed ex vivo tissue analyses. Methods: Patients (n=172) with end-stage knee OA were randomized to 4 groups and treated for 4 weeks prior to knee replacement surgery: celecoxib 2dd200mg, naproxen 3dd250mg, celecoxib 2dd200mg stopped 3 days prior to surgery, or no-treatment. Cartilage and synovial tissue collected during surgery were analyzed ex vivo, with cartilage proteoglycan release as primary outcome. Additionally, several markers of synovial inflammation and clinical effects were determined. Results: Data of 138 patients could be analyzed, 34 patients were lost for several reasons. The expression of COX-2 in both cartilage and synovial tissue was statistically significant decreased in patients treated with celecoxib (p=0.017 and p=0.001) respectively), indicating the drug has reached the knee joint within the treatment period. Nonetheless, no significant effect on proteoglycan release, retention or content was found. Synovial inflammation markers did not show any statistically significant decrease although nitric oxide levels in celecoxib treated patients suggest a beneficial effect of celecoxib compared to no treatment. WOMAC scores did not statistically significant improve after treatment; though celecoxib treated patients reported a slightly higher WOMAC pain score compared to non-treated patients. Conclusion: No direct effect on cartilage upon short term in vivo treatment of knee OA patients with celecoxib could be detected, although decreased expression of COX-2 confirmed its intra-articular availability. Effects on synovial inflammatory mediators and clinical outcome seemed only limited. As such the previous reported disease modifying effects of celecoxib in in vitro and pilot clinical studies could not unambiguously be confirmed.

Proteomics to predict the response to tumour necrosis factor-α inhibitors in rheumatoid arthritis using a supervised cluster-analysis based protein score

Objective: In rheumatoid arthritis (RA), it is of major importance to identify non-responders to tumour necrosis factor-α inhibitors (TNFi) before starting treatment, to prevent a delay in effective treatment. We developed a protein score for the response to TNFi treatment in RA and investigated its predictive value. Method: In RA patients eligible for biological treatment included in the BiOCURA registry, 53 inflammatory proteins were measured using xMAP® technology. A supervised cluster analysis method, partial least squares (PLS), was used to select the best combination of proteins. Using logistic regression, a predictive model containing readily available clinical parameters was developed and the potential of this model with and without the protein score to predict European League Against Rheumatism (EULAR) response was assessed using the area under the receiving operating characteristics curve (AUC-ROC) and the net reclassification index (NRI). Results: For the development step (n = 65 patient), PLS revealed 12 important proteins: CCL3 (macrophage inflammatory protein, MIP1a), CCL17 (thymus and activation-regulated chemokine), CCL19 (MIP3b), CCL22 (macrophage-derived chemokine), interleukin-4 (IL-4), IL-6, IL-7, IL-15, soluble cluster of differentiation 14 (sCD14), sCD74 (macrophage migration inhibitory factor), soluble IL-1 receptor I, and soluble tumour necrosis factor receptor II. The protein score scarcely improved the AUC-ROC (0.72 to 0.77) and the ability to improve classification and reclassification (NRI = 0.05). In validation (n = 185), the model including protein score did not improve the AUC-ROC (0.71 to 0.67) or the reclassification (NRI = −0.11). Conclusion: No proteomic predictors were identified that were more suitable than clinical parameters in distinguishing TNFi non-responders from responders before the start of treatment. As the results of previous studies and this study are disparate, we currently have no proteomic predictors for the response to TNFi.

SAT0126 Comorbidities after Daily Concomitant Treatment with 10mg Prednisone or Placebo in The 2-Year Computer Assisted Management in Early Rheumatoid Arthritis Trial-Ii: Table 1.

Background In the second Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA–II) trial, patients initiated treatment with methotrexate (MTX) with randomized 10 mg/d prednisone (pred) or placebo (plac), given for 2 years [1]. Significantly more patients in the MTX+pred strategy arm than in the MTX+plac arm were erosion free at 2 years, and disease activity improved faster. The frequency of adverse events (AE) during the 2 year trial was comparable between the groups. There is paucity of data on long-term AEs after treatment with medium dose of glucocorticoids, however. Objectives To investigate the incidence of long-term AEs/comorbidities in early rheumatoid arthritis patients, who had been treated additionally with pred10 mg/day or plac in CAMERA-II. Methods After the 2 year trial, patients were followed according to a protocol in clinical care. The occurrence of AEs/comorbidities and the use of pred (it was the strategy to taper and stop it) was collected retrospectively from the medical charts. The incidence of long-term AEs/comorbidities in the former MTX+pred group was tested versus that in the former MTX+plac group using Fishers Exact tests. Results Of the 236 patients included in the CAMERA-II trial, follow-up data was available of 218 patients: MTX+pred N=107, MTX+plac N=111; no longer followed according to protocol N=18. The median follow-up time after the end of the 2-year trial period was 6 (range 0–9) and 6 (0–11) years, respectively. 86 (80%) patients treated with pred could discontinue it after a median of 9 months after the end of the trial end. The percentage of patients with AEs/comorbidities is shown in Table 1. No statistically significant differences between the two groups were found.Table 1. Percentage of new onset AEs/comorbidities after the trial in the former pred vs former plac group Comorbidity MTX + pred (N=107) MTX + plac (N=111) p-value ≥1 comorbidity 36 36 1.00 Hypertension 4 10 0.11 Diabetes Mellitus type II 3 2 0.68 Cardiovascular disease 13 8 0.27 Peptic ulcer 1 0 0.49 Cataract 8 7 0.80 Glaucoma 0 1 1.00 Fracture 11 14 0.55 Osteonecrosis 0 0 – Mortality 10 6 0.33 Conclusions Of patients in the MTX+pred group during CAMERA-II, 80% could discontinue pred after the trial. There was no increased incidence of long-term AEs/comorbidities in the former MTX+pred group. References Bakker MF, Jacobs JWG, Welsing PMJ, et al. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 2012;156:329–39. Disclosure of Interest None declared

A3.5 IL-13-mediated STAT6 dependant modulation of fibrosis and effects of MIR135B

Background and objectives Systemic sclerosis is an autoimmune disease that is characterised by inflammation and fibrosis. Perivascular infiltrates of T cells are found in the skin and the T cell bias is predominantly Th2 with an increase of IL-13 in the skin and blood. We have found that Interleukin-13 (IL-13) is elevated and mediates increase deposition of ECM in SSc but the underlying molecular mechanism of IL-13 mediated ECM increases is unknown. The aim here was to investigate the molecular mechanism of IL-13 mediated ECM induction in dermal fibroblasts and to determine the role of miR135b, a miR with a putative role in IL-13 effects. Methods Dermal fibroblasts were taken from punch biopsies from healthy controls or SSc patients and cultured in vitro with or without the addition of recombinant IL-13. siRNA was carried out with 100nM of siRNA against STAT6 with scramble siRNA using DharmaFECT reagent. Collagen1A1, TIMP-1 and alphaSMa gene expression was analysed by qRT-PCR with 18S as the internal housekeeping gene for normalisation. miR135b mimics were transfected into dermal fibroblasts using DharmaFECT and a control miR was also transfected for comparison. Bleomycin was injected into mice to cause skin fibrosis or saline control for comparison and the mice were sacrificed and skin biopsies taken and immunohistochemistry was performed with specific IL-13 antibodies and florescent labelled secondary antibodies and imaged using confocal microscopy. Results IL-13 dose dependently increased the levels of collagen1A1 in dermal fibroblasts. However, there was no increase in the other pro fibrotic molecules TIMP-1 or the myofibroblast marker alpha smooth muscle actin by IL-13 by qPCR. Furthermore there was no increase in the pro fibrotic molecule TGF-β1. siRNA mediated silencing of STAT6 in dermal fibroblasts attenuated the induction of collagen1A1 mediated by IL-13 indicating STAT6 is crucial in this effect. Prediction software suggested that STAT6 has a binding site for miR135b in its 3’UTR and transfection of miR135b reduced STAT-6 mediated collagen induction in these cells. Measurement of miR135 post transfection confirmed that the miR was transfected into the cells. Bleomycin induced fibrosis in the mouse model was used and using immunohistochemistry it was found that in the skin IL-13 was elevated compared to vehicle treated mice, indicating T cell infiltration in this model of systemic sclerosis. Conclusions IL-13 utilises STAT6 to mediate induction of collagen in dermal fibroblasts. STAT6 is an important molecule in mediating fibrosis and is targeted by miR135b and elevated levels of miR135b diminishes STAT6-mediated effects in these cells. IL-13 from T cells is also elevated in bleomycin induced fibrosis models.

THU0081 Towards Individualized Risk Determination in RA: A Prediction Model for TNFI Discontinuation within the First Year After Start

Background TNF-alpha inhibitor (TNFi) treatment has dramatically improved the outcome of RA patients. A substantial number of patients, however, fails to clinically respond to this therapy or experiences adverse-effects that necessitate discontinuation of therapy. In that sense, treatment success could be envisioned as a matter of balance between drug efficacy and tolerability. Prediction of discontinuation gives insight in patients at risk for suboptimal treatment success, and possibly factors that interacts the decision making of physician and patient. Objectives To predict TNFi discontinuation within the first year of use in an observational cohort and gain more insight in parameters predictive of treatment success. Methods Data was used from the Biologicals and Outcome Compared and predicted Utrecht region in Rheumatoid Arthritis (BiOCURA) cohort. Eight hospitals of the Society for Rheumatology Research Utrecht included patients eligible for biological treatment, which were followed up to one year after start of this treatment. A univariate preselection (p<0.2) was performed to enter variables in the multivariable cox-regression model with backward selection (p<0.1). To develop a quick tool for clinical practice, the linear predictor was simplified by adjusting the coefficients to usable scores. Results After one year of follow-up of 192 TNFi patients, 75 (39%) discontinued treatment, because of inefficacy (64%) or side-effects (33%). Discontinuation was predicted by a combination of female gender (HR=2.1, p=0.02), currently smoking (HR=1.8, p=0.03), RF positivity (HR=0.67, p=0.10), high VAS-GH score (HR=1.02/mm, p<0.01) and higher number of previous biological DMARDs (HR=1.5/biological, p<0.01). A simplified score for use in clinical practice was made (see table). For each of the five variables a patient scores points. The sum of these scores can determine if there is an absolute chance of discontinuation within the first year of 67% (score >7.00) or 83% (score >7.75). Analyses of the high versus low risk patients revealed no different reasons for discontinuation (p=0.27 and 0.90 for different cut-offs respectively). Interestingly, the course over time of DAS28 and DAS28-inflammation and pain component in high risk (score >7.00) versus low risk patients, revealed differences that put discontinuing in a more subjective context: Although absolute DAS28 scores were higher over time for the high risk patients (0.27-0.75), these differences could be explained by a higher relative pain component of the DAS28, which was increased up to 1.3 fold three months after start (p<0.01).Table 1 Points Female gender, yes 3.0 Currently smoking, yes 2.0 RF negativity, yes 1.5 No. of prev. biologicals, per biological 1.5 VAS-GH, per 10mm 0.2 Total … Conclusions TNFi discontinuation within the first year of use in an observational cohort can be predicted by a simple prediction score. The reported pain by patients is probably an underestimated factor in the clinical decision of discontinuation. To investigate if these findings are reproducible, validation will be performed at short notice when 100 subsequent TNFi treated patients are included in the BiOCURA cohort (currently n=75). Disclosure of Interest None declared