Anton Wulf Christensen

Pain Sensitisation in Women with Active Rheumatoid Arthritis: A Comparative Cross-Sectional Study

Objectives. In some rheumatoid arthritis (RA) patients, joint pain persists without signs of inflammation. This indicates that central pain sensitisation may play a role in the generation of chronic pain in a subgroup of RA. Our aim was to assess the degree of peripheral and central pain sensitisation in women with active RA compared to healthy controls (HC). Methods. 38 women with active RA (DAS28 > 2.6) and 38 female HC were included in, and completed, the study. Exclusion criteria were polyneuropathy, pregnancy, and no Danish language. Cuff Pressure Algometry measurements were carried out on the dominant lower leg. Pain threshold, pain tolerance, and pain sensitivity during tonic painful stimulation were recorded. Results. Women with active RA had significantly lower pain threshold (p < 0.01) and pain tolerance (p < 0.01) than HC. The mean temporal summation- (TS-) index in RA patients was 0.98 (SEM: 0.09) and 0.71 (SEM: 0.04) in HC (p < 0.01). Conclusion. Patients with active RA showed decreased pressure-pain threshold compared to HC. In addition, temporal summation of pressure-pain was increased, indicating central pain sensitization, at least in some patients. Defining this subgroup of patients may be of importance when considering treatment strategies.

Non-nociceptive pain in rheumatoid arthritis is frequent and affects disease activity estimation: cross-sectional data from the FRAME study

Background: The painDETECT questionnaire (PDQ) is a mechanism-based pain classification tool assigning patients to one of three categories depending on the quality of the experienced pain. Patients with non-nociceptive pain score high on the PDQ. The objective was to assess the proportions of the three PDQ classification groups in patients with rheumatoid arthritis (RA) and to explore differences in clinical characteristics. Method: RA patients initiating or escalating their RA therapy were included prospectively and underwent a thorough examination programme. Low (PDQ score < 13), medium (PDQ score 13–18), and high (PDQ score > 18) scores indicate nociceptive, unclear/possible neuropathic, or neuropathic pain mechanisms, respectively. Results: The 102 included patients were classified into the following PDQ classification groups: low = 65%, medium = 23%, and high = 12%. Patients in the medium and high PDQ groups scored worse on indicators of anxiety, depression, disability, mental health-related quality of life, pain, and fatigue. They also had more tender points and an RA disease activity score based on 28 joints (DAS28) where a higher fraction of the composite score pertained to non-inflammatory factors compared to patients in the low PDQ classification group. There were no differences in objective inflammatory indices across groups. Multiple regression analysis demonstrated that the tender joint count (TJC) and the 36-item Short Form Health Survey (SF36) mental component summary (MCS) score were independently associated with the PDQ score. Conclusions: In patients initiating or intensifying medical treatment for their RA, non-nociceptive pain (PDQ score ≥ 13) is common. In these patients, the pain mechanisms result in increased disease activity scores on a non-inflammatory basis.

Temporal summation of pain and ultrasound Doppler activity as predictors of treatment response in patients with rheumatoid arthritis: protocol for the Frederiksberg hospitals Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study

Introduction Chronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy. Method and analysis 120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment. Ethics and dissemination This study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.

Can the painDETECT Questionnaire score and MRI help predict treatment outcome in rheumatoid arthritis: protocol for the Frederiksberg hospital's Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study

Introduction Pain in rheumatoid arthritis (RA) is traditionally considered to be of inflammatory origin. Despite better control of inflammation, some patients still report pain as a significant concern, even when being in clinical remission. This suggests that RA may prompt central sensitisation—one aspect of chronic pain. In contrast, other patients report good treatment response, although imaging shows signs of inflammation, which could indicate a possible enhancement of descending pain inhibitory mechanisms. When assessing disease activity in patients with central sensitisation, the commonly used disease activity scores (eg, DAS28-CRP (C reactive protein)) will yield constant high total scores due to high tender joint count and global health assessments, whereas MRI provides an isolated estimate of inflammation. The objective of this study is, in patients with RA initiating anti-inflammatory treatment, to explore the prognostic value of a screening questionnaire for central sensitisation, hand inflammation assessed by conventional MRI, and the interaction between them regarding treatment outcome evaluated by clinical status (DAS28-CRP). For the purpose of further exploratory analyses, dynamic contrast-enhanced MRI (DCE-MRI) is performed. Method and analysis The painDETECT Questionnaire (PDQ), originally developed to screen for a neuropathic pain component, is applied to indicate the presence of central sensitisation. Adults diagnosed with RA are included when either (A) initiating disease-modifying antirheumatic drug treatment, or (B) initiating or switching to biological therapy. We anticipate that 100 patients will be enrolled, tested and reassessed after 4 months of treatment. Data collection includes Clinical data, conventional MRI, DCE-MRI, blood samples and patient-reported outcomes. Ethics and dissemination This study aims at supporting rheumatologists to define strategies to reach optimal treatment outcomes in patients with RA based on chronic pain prognostics. The study has been approved by The Capital region of Denmarks Ethics Committee; identification number H-3-2013-049. The results will be published in international peer-reviewed journals.

Reliability of pain measurements using computerized cuff algometry: a DoloCuff reliability and agreement study

Computerized pneumatic cuff pressure algometry (CPA) using the DoloCuff is a new method for pain assessment. Intra‐ and inter‐rater reliabilities have not yet been established. Our aim was to examine the inter‐ and intrarater reliabilities of DoloCuff measures in healthy subjects.

Pain mechanisms and ultrasonic inflammatory activity as prognostic factors in patients with psoriatic arthritis: protocol for a prospective, exploratory cohort study.

Introduction Persistent pain is a major concern for patients with psoriatic arthritis (PsA). Pain may be due to inflammatory activity or augmented central pain processing. Unawareness of the origin and mechanisms of pain can lead to misinterpretation of disease activity (by composite scores) and erroneous treatments. Ultrasonography (US) is a highly sensitive method to detect tissue inflammation. Evaluating pain mechanisms in relation to US measures may prove valuable in predicting response to treatment in PsA. Aims To study the association and prognostic value of pain mechanisms, ultrasonic activity and clinical outcomes in patients with PsA who intensify antirheumatic treatment. Methods and analyses 100 participants >18 years of age with PsA who initiate or switch antirheumatic treatment (biologicals and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs)) will be prospectively recruited from outpatient clinics in Copenhagen. All data (demographics, clinical, imaging, blood samples and patient-reported outcomes) will be collected at baseline and after 4 months. Pain is assessed by the PainDETECT Questionnaire, Visual Analogue Scale for pain, Swollen to Tender Joint Count Ratio, Widespread Pain Index and tender point examination. The association between pain variables and clinical/US characteristics will be described by correlation analyses. The predictive value of pain measures and baseline US scores on treatment response will be analysed with regression models. Outcomes are composite and clinical, as well as patient reported. Ethics and dissemination The study is approved by the ethics committee of the Capital Region of Denmark (H-15009080) and has been designed in cooperation with patient research partners. The study is registered at clinicaltrials.gov (number NCT02572700). Results will be disseminated through publication in international peer-reviewed journals. Trial registration number NCT02572700, Pre-results.

FRI0099 Indications of Reversibility of Central Sensitization According To The Paindetect Questionnaire in Patients with Rheumatoid Arthritis: Results from The Prospective Frame-Cohort Study

Background Pain in rheumatoid arthritis (RA) is typically regarded as related to on-going synovial inflammation in peripheral joints. However, in a subgroup of patients evidence indicates that pain can become an entity of its own caused by central sensitization (CS), elicited by but in time not directly related to ongoing inflammation. The painDETECT questionnaire (PDQ) was developed to differentiate neuropathic pain from unclear and non-neuropathic pain. In several studies it has been used to indicate CS owing to similarities in somatosensory profiles. Magnetic resonance imaging (MRI) can be used as an objective inflammation marker, quantified by the RA MRI Score (RAMRIS). Objectives To evaluate the prognostic value of a PDQ score >18 on DAS28 response in RA patients taking a possible interaction with inflammation defined by RAMRIS synovitis scores into account. Methods RA patients were included when they were to: 1) initiate a disease modifying antirheumatic drug (DMARD) or 2) initiate or switch a biological agent. At baseline and after 4 month of follow up patients went through an examination program incl. standard demographics, clinical examination, hand MRI, patient reported outcomes (incl. PDQ), and blood samples. Least-Squares Mean change (95% CI) was calculated using ANCOVA adjusting for the value at baseline. Multivariable regressions with DAS28 or RAMRIS synovitis change as outcome were performed to determine the prognostic variables. The model included PDQ-category, RAMRIS synovitis score and their interaction. Possible confounders were: gender, disease duration, baseline DAS28, and initiation group. PDQ score was interpreted as: >18 indication of CS, 13–18 unclear pain mechanism, <13 nociceptive pain. Pain classification consistency was explored. Results 102 patients were included, 75 had an MRI scan performed. Mean changes stratified by PDQ-group are presented in the table showing the greatest changes in the CS-group (>18). Only baseline DAS28 was a significant predictor of DAS28 change (P<0.001) with a β-estimate (95%CI) of -0.65 (-88;-0.41). Baseline DAS28 and RAMRIS synovitis were significant predictors of RAMRIS synovitis change (P=0.01, P=0.02) with β-estimates of -0.67 (-1.17;-0.17) and -0.19 (-0.35;-0.03). Among the 12 patients with indication of CS (>18) at baseline all had changed classification-group at follow-up (8 to nociceptive pain and 4 to unclear). Conclusions In this pragmatically sampled population of RA patients, pain classification by PDQ at treatment initiation had no prognostic value with regard to change in DAS28 or RAMRIS synovitis. In contrast, all patients classified with indication of CS by PDQ at baseline changed classification group and were even to gain most from treatment start in net changes. This might indicate that in RA, CS reflects normal neuroplasticity that is reversible with reduction of inflammation. References Koroschetz J, et al. Fibromyalgia and neuropathic pain-differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol 2011;11:55 Disclosure of Interest None declared

OP0291 How Medication History and Average Disease Duration Modify Treatment Effect in Randomised Trials Using Targeted Therapies for Rheumatoid Arthritis: A Meta-Epidemiological Study: Table 1.

Background Randomised trials that have tested targeted therapies (targeted synthetic disease modifying antirheumatic drugs, tsDMARDs and biological disease modifying antirheumatic drugs, bDMARDs) for rheumatoid arthritis (RA) vary in several of their trial and participant characteristics [1], but little is known about whether these characteristics influence the overall effect of the therapies in the reported trials. Objectives To determine whether trial and participant characteristics modify the treatment response when testing the efficacy of targeted therapies (in contrast to comparator) for RA. Methods We conducted a meta-epidemiological study of all trials testing a dosage of a targeted therapy approved by regulatory authorities for the treatment of RA. Included trials reported ACR20 data at months 3-6 and used an add-on design. Anakinra and open-label trials were not included. Odds ratios (ORs) were calculated from the response rates and compared among the trial/participant characteristics of interest. Statistical analyses were performed using SAS v 9.3 (REML based models). Comparisons between strata are presented as the Ratio of Odds Ratios (ROR). Results Sixty-two trials (19,923 RA patients) were included in the primary analyses using ACR20 as the outcome (table 1). Overall, targeted therapies constituted an effective treatment (OR 3.96 95% confidence interval 3.41 to 4.60). The net benefit of targeted therapies was lower in trials including “DMARD-naïve” patients compared with both “DMARD inadequate responders” (ROR=0.45, 0.31 to 0.66) and “biologic inadequate responders” (0.50, 0.29 to 0.87) trials (test for interaction: p=0.0002). Longer disease duration of the trial population was also statistically significantly associated with a higher likelihood of responding to treatment (β=1.05, 1.00 to 1.11 ORs per year). Analyses conducted using DAS28-remission as the outcome supported the above-mentioned findings.Table 1. Results of the stratified meta-analyses with ACR20 as the dependent variable Variable Trial characteristics Trials OR (95% CI) p-interaction Overall 62 3.96 (3.41 to 4.60) N.A. Medication history 0.0002 DMARD-naïve 8 1.97 (1.39 to 2.79) DMARD-inadequate responders 49 4.34 (3.75 to 5.01) Bio-inadequate responders 5 3.92 (2.58 to 5.97) Variable Participant characteristics Trials Coefficient (95% CI) p-value Baseline disease duration (years) 62 1.05 (1.00 to 1.11) 0.03 Conclusions Trial evidence suggests that using targeted therapies add the greatest net benefit in patients who are inadequate responders to previous DMARDs or biological agents, and trials including patients with longer disease duration. These findings justify that all RA patients should be exposed to DMARD treatment before introduction of a bDMARD is considered. References Rahman MU, Buchanan J, Doyle MK, et al. Changes in patient characteristics in anti-tumour necrosis factor clinical trials for rheumatoid arthritis: results of an analysis of the literature over the past 16 years. Ann Rheum Dis 2011 Sep;70(9):1631-40. Acknowledgements This study is supported financially by The Oak Foundation, Selsbjerg Holding and Region Hovedstadens Forskningsfond. Disclosure of Interest None declared

THU0305 Fatigue is Correlated to Pain Mechanism Rather than to Inflammatory Load in Patients with Rheumatoid Arthritis: A Descriptive Cross-Sectional Danbio Registry Survey

Background In patients with rheumatoid arthritis (RA), patient reported outcomes (PROs) are sometimes reported to be refractory to therapies targeting anti-inflammatory pathways, which may be due to influence of central pain mechanisms. The painDETECT Questionnaire (PDQ), which is a validated questionnaire developed to detect neuropathic pain, assigns a score to the patient. Since its development the PDQ has also been used to link the pain phenotypic similarities of a neuropathic pain and central sensitization in osteoarthritis and fibromyalgia, and may be used as well in RA. Objectives To examine whether fatigue is closer associated to the PDQ-score than CRP in patients with RA. Methods An electronic version of the PDQ was added to the DANBIO touchscreens in the waiting rooms at 22 of 24 departments of Rheumatology in Denmark for a period of six months. Patient consent was obtained and corresponding data on patients diagnosed with RA in the DANBIO database were extracted. A PDQ score >18 was interpreted as an indication of predominant central pain mechanisms, 13-18 as unclear and <13 as nociceptive pain. Interactions between strata were based on Kruskal-Wallis test and correlations based on Spearman correlation coefficients. Results Out of 15978 patients invited to participate in the survey, 9024 were diagnosed with RA. Of these, 4387 patients agreed to fill in the PDQ and 3826 patients completed it. Patients with higher PDQ-scores had higher VAS-fatigue, DAS28, VAS-global health and more tender and swollen joints (Table 1). VAS-fatigue correlated moderately with the PDQ-score (Rho=0.48), but not with CRP (Rho=0.09) as shown in Table 2. Table 1 Variable PDQ-score <13 PDQ-score 13-18 PDQ-score >18 p-interaction n Median (IQR) n Median (IQR) n Median (IQR) VAS-fatigue 1965 34 (17–57) 831 54 (34–72) 712 72 (54–85) <0.0001 DAS28 1734 2.4 (1.9–3.3) 714 3 (2.3–3.9) 598 3.7 (2.8–4.7) <0.0001 VAS-GH 1973 29 (15–53) 833 51 (31–68) 716 70 (52–84) <0.0001 TJC28 1859 0 (0–2) 776 1 (0–5) 660 4 (0–9) <0.0001 SJC28 1851 0 (0–1 ) 772 0 (0–2) 659 0 (0–2) <0.0001 CRP 1836 4 (2–9) 757 4 (1–9) 638 4 (2–10) 0.07 DAS28, Disease activity score (28 joint count); PDQ, painDETECT questionnaire; SJC28, 28 swollen joint count; TJC28, 28 tender joint count; VAS-GH, patient global health score on a visual analogue scale (0–100). Table 2 Variable Correlations for VAS-fatigue rho p-value n PDQ-score 0.48 <0.0001 3508 CRP 0.09 <0.0001 3636 Conclusions These results suggest that fatigue, in patents with RA, shows a closer association with PDQ (indicator of clinical features of augmented central pain processing) than with CRP (indicator of inflammatory load). Disease models other than peripheral inflammatory driven models are probably needed to fully understand the mechanisms underlying individual differences in pain characteristics and might allow for a more individual approach to treatment. Acknowledgements This study is supported financially by The Oak Foundation and Selsbjerg Holding. The authors would like to acknowledge the participating Departments of Rheumatology, DANBIO and Zitelab for their assistance. Disclosure of Interest None declared

THU0326 Pain Mechanisms in Patients with Inflammatory Arthritis: A Nationwide Cross-Sectional Danbio Registry Survey

Background Central pain mechanisms may be prominent in subsets of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and other spondyloarthritis (SpA). The validated painDETECT Questionnaire (PDQ) was developed to detect neuropathic pain by assigning a score to the patient. Numerous studies in osteoarthritis and fibromyalgia have used the PDQ to assess central sensitization linking the pain phenotypic similarities of neuropathic pain and central sensitization together. Data are emerging within RA and SpA. Objectives Based on PDQ classification, to identify pain phenotypes (nociceptive vs. central mechanisms) in Danish patients with inflammatory arthritis; to determine prevalence and assess association to present inflammation. Further to characterize the different pain populations. Methods An electronic version of the PDQ was included onto the DANBIO touch screens in the waiting rooms at 22 of 24 departments of Rheumatology in Denmark for six months. Patients diagnosed with RA, PsA or SpA were invited to participate. Consent was obtained. Patients who declined participation were asked, whether it was due to being pain-free. Corresponding clinical data and patient reported outcomes (PROs) were obtained from DANBIO. A PDQ score >18 was interpreted as an indication of predominant central pain mechanisms, 13-18 as unclear and <13 as nociceptive pain. Kruskal-Wallis test, Chi square test and Spearman (Rho) correlations between PDQ score and selected variables were performed. Results Of 15978 invited patients, 52% had a VAS pain ≥30mm. A total of 1927 patients were pain-free, 7918 patients agreed to fill in the PDQ and 7054 completed it (RA: 3826, PsA: 1180, SpA: 1093, unspecified: 955). VAS pain ≥30mm was present in 59.5%/ 67%/ 67% of RA/ PsA/ SpA pts. Prevalence of the PDQ classification-groups (<13/ 13-18/ >18) were: RA; 56%/ 24%/ 20%. PsA; 45%/ 27%/ 28%. SpA; 55%/24%/ 21%. More patients with PsA had PDQ score >18 compared to RA and SpA (p<0.001). Characteristics (pct. or median) for the PDQ classification-groups across diagnoses are reported in the table. Overall correlations (Rho) across diagnoses were; CRP=0.01; VAS pain=0.52; VAS global health (GH)=0.53. For RA and PsA; DAS28-crp=0.42; tender joint count-28=0.34; swollen joint count-28=0.15. For SpA; BASDAI=0.58. P<0.001 (except for CRP, p=0.38). Analyzing each diagnosis separately revealed the same tendencies. Conclusions In a cohort of >7000 arthritis patients, pain was present in