Hans Christian Horn

Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial

Objectives An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months. Methods In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6–9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward. Results Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7–5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7–4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008<p<0.014, number-needed-to-treat: 4.0–5.4). Twelve months HAQ, SF12PCS and EQ-5D improvements were most pronounced in the adalimumab group. Treatments were well tolerated. Conclusions Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP<3.2 treatment target, but improved DAS28CRP, remission rates, function and quality of life in DMARD-naïve ERA.

A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial

Objectives To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. Methods In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. Results Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months’ follow-up, with mean change scores of −3.7 (median −3.0), −2.2 (−1) and −5.3 (−4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann–Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months’ follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001–0.002 and p=0.062–0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. Conclusions A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.

Shared care or nursing consultations as an alternative to rheumatologist follow-up for rheumatoid arthritis outpatients with low disease activity—patient outcomes from a 2-year, randomised controlled trial

Objectives To compare patient outcomes of three regimes of follow-up care for rheumatoid arthritis (RA) outpatients with low disease activity. Methods RA outpatients (n=287) with Disease Activity Score (DAS28-CRP)<3.2 and Health Assessment Questionnaire<2.5 from two Danish rheumatology clinics were randomised to 2-year follow-up by either: (1) planned rheumatologist consultations, (2) shared care without planned consultations or (3) planned nursing consultations. The primary outcome was change in disease activity. DAS28-CRP, Health Assessment Questionnaire, visual analogue scale (VAS)-pain, fatigue, global health, confidence and satisfaction, quality-of-life by the Short Form 12 and self-efficacy measured by the RA Self-Efficacy questionnaire and the Arthritis Self-Efficacy Scale, were recorded annually and safety measures were recorded. x-Rays of hands and feet were taken at baseline and at 2-year follow-up. Mixed effect models were used to explore differences between the three groups over time. Results At 2-year follow-up, the group allocated to nursing consultations had lower disease activity than the group that underwent rheumatologist consultations (DAS28-CRP −0.3, p=0.049). The nursing group increased their self-efficacy (Arthritis Self-Efficacy Scale 18.8, p=0.001), confidence (10.7, p=0.001) and satisfaction (10.8, p<0.001) compared with the rheumatologist group. The shared care group reported a transient lower satisfaction compared with the rheumatologist group after 1 year (−8.8, p=0.004). No statistically significant differences were seen in other outcome variables. Conclusions It is safe to implement shared care and nursing consultations as alternatives to rheumatologist consultations for RA outpatients with low disease activity without deterioration in disease control. Nursing consultations can enhance patients’ self-efficacy, confidence and satisfaction.

Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis.

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo–adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.

OP0115 Clinical and radiological outcome in outpatients with rheumatoid arthritis followed by medical, nursing or shared care – a two year randomised controlled trial

Background Studies have indicated that follow-up by nursing consultations or different versions of shared care are not inferior to medical follow-up in controlling disease activity in patients with rheumatoid arthritis (RA) (1,2). Objectives To explore whether RA patients disease status, function and progression of erosions would differ depending on the type of follow-up care: 1) planned nursing consultations every three months, 2) shared care with no planned consultations but access to the General Practitioner and a nurse-led telephone help-line or 3) traditional rheumatologist initiated follow-up. Methods In a randomised controlled trial 287 adult outpatients in stable non-biological treatment, DAS-28<3.2, HAQ<2.5 and at least 18 months of disease duration were allocated to one of the three types of follow-up care for the following two years. DAS-28, HAQ, VAS-fatigue and pain were assessed at enrollment, one and two years follow-up. Clinical evaluation was performed yearly by a blinded investigator. Mixed effect models were used to examine the data. Progression of erosions in hands and feet from x-rays at baseline and two-years follow-up were explored in logistic regression analysis controlling for erosions and positive anti-CCP at baseline. Results Across all participants a significant increase was seen in DAS-28 (0.51, p<0.001), HAQ (0.086, p=0.012) and pain (4.26, p=0.019) from baseline till two-years follow-up. VAS-fatigue remained stable during the two years. No significant differences were seen between the groups in these outcome measures or in the number of participants with DAS-28>3.2 at two-year follow up (28 (29%), 19 (20%) and 17 (18%) of the participants in the medical, shared care and nursing group respectively). The odds ratio for progression on x-rays in the shared care and the nursing group did not differ from the medical group (shared care OR 0.56, p=0.264 (CI: 0.28-1.55), nursing group OR 1.03, p=0.945 (CI: 0.44-2.56)). There was no significant difference between the groups in the number of adverse events. Conclusions In patients with established RA and low disease activity it is considered to be safe to implement shared care and nursing consultations without differences in disease control compared to traditional medical follow-up. References [1] Hewlett S, Kirwan J, Pollock J, Mitchell K, Hehir M, Blair PS et al. Patient initiated outpatient follow up in rheumatoid arthritis: six year randomised controlled trial. BMJ 2005; 330(7484):171. [2] Hill J, Thorpe R, Bird H. Outcomes for patients with RA: A rheumatology nurse practitioner clinic compared to standard outpatient care. Musculoskeletal Care 2003; 1(1):5-20. Disclosure of Interest None Declared

Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo-controlled trial

Introduction An unbalanced intestinal microbiota may mediate activation of the inflammatory pathways seen in psoriatic arthritis (PsA). A randomised, placebo-controlled trial of faecal microbiota transplantation (FMT) infused into the small intestine of patients with PsA with active peripheral disease who are non-responsive to methotrexate (MTX) treatment will be conducted. The objective is to explore clinical aspects associated with FMT performed in patients with PsA. Methods and analysis This trial is a randomised, two-centre stratified, double-blind (patient, care provider and outcome assessor), placebo-controlled, parallel-group study. Eighty patients will be included and randomised (1:1) to either placebo (saline) or FMT provided from an anonymous healthy donor. Throughout the study, both groups will continue the weekly self-administered subcutaneous MTX treatment, remaining on the preinclusion dosage (15–25 mg/week). The clinical measures of psoriasis and PsA disease activity used include the Short (2-page) Health Assessment Questionnaire, the Dermatology Quality of Life Index, the Spondyloarthritis Research Consortium of Canada Enthesitis Index, the Psoriasis Area Severity Index, a dactylitis digit count, a swollen/tender joint count (66/68), plasma C reactive protein as well as visual analogue scales for pain, fatigue and patient and physician global assessments. The primary end point is the proportion of patients who experience treatment failure during the 6-month trial period. The number of adverse events will be registered throughout the study. Ethics and dissemination This is a proof-of-concept clinical trial and will be performed in agreement with Good Clinical Practice standards. Approvals have been obtained from the local Ethics Committee (DK-S-20150080) and the Danish Data Protection Agency (15/41684). The study has commenced in May 2017. Dissemination will be through presentations at national and international conferences and through publications in international peer-reviewed journal(s). Trial registration number NCT03058900; Pre-results.

Clinical characteristics of importance to outcome in patients with axial spondyloarthritis: protocol for a prospective descriptive and exploratory cohort study

Introduction Spondyloarthritis (SpA) is a heterogeneous spectrum of rheumatic diseases with either predominantly axial inflammatory symptoms of the spine and sacroiliac joints or predominantly peripheral arthritis. The two main entities of axial SpA (axSpA) are ankylosing spondylitis or non-radiographic axSpA (nr-axSpA). Tumour necrosis factor-α inhibitors have revolutionised the treatment of patients with axSpA who failed to respond to non-steroidal anti-inflammatory drugs and physical therapy. Chronic pain is common in patients with SpA and may still persist despite the lack of signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in SpA. The painDETECT Questionnaire (PDQ) is a screening tool developed to detect neuropathic pain components. The primary objective is to explore the prognostic value of the PDQ regarding treatment response in patients with axSpA 3 months after initiating a biological agent. Secondary aim is to evaluate the impact of extra-articular manifestations, comorbidities and patient-reported outcomes and elucidate if these factors influence treatment response. Method and analysis We will include 60 participants (≥18 years of age) diagnosed with axSpA independent of main entity, who initiate or switch treatment of a biologic. Data will be collected at baseline and at endpoint following Danish clinical practice (≥3 months) of treatment with biologics. We will explore whether the PDQ and other phenotypical patient characteristics are prognostically important for response to biological therapy according to established response criteria like 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (50%) and Ankylosing Spondylitis Disease Activity Score. Ethics and dissemination The study is approved by the Region of Southern Denmark’s Ethics committee (S-20160094) and has been designed in cooperation with patient representatives. The study is registered at clinicaltrials.gov (NCT02948608, pre-results). Dissemination will occur through publication(s) in international peer-reviewed journal(s).

The Impact of Patient- Reported Flares on Radiographic Progression in Rheumatoid Arthritis Patients with Low-Disease Activity: secondary analyses from a randomized trial

This free journal suppl. entitled: Special Issue: 2014 ACR/ARHP Annual Meeting Abstract Supplement

FRI0148 Remission rates increase substantially by adding adalimumab to methotrexate and intra-articular glucocorticoid in patients with early rheumatoid arthritis - 1-year results of investigator-initiated, double-blinded randomized clinical trial (OPERA)

Background In the CIMESTRA Study patients with early rheumatoid arthritis (RA) were treated with methotrexate (MTX) and intra-articular glucocorticoid. This led to results comparable to biological trials with 34%/28% of pts in DAS28/ACR remission after 1 year (1,2). Objectives We studied if addition of adalimumab (ADA) to the CIMESTRA strategy is of further therapeutic benefit. Methods DMARD naïve early RA patients with disease duration <6 months (n=180) were randomized 1:1 to MTX 7.5 mg weekly + ADA 40 mg eow or MTX + placeboADA (PLA). MTX was increased to 20 mg/week within two months. Treatment target was low disease activity (DAS28(CRP) <3.2). Injections of triamcinolone were given into swollen joints (max. 4 joints/4 ml/visit). Oral prednisolone was not allowed. Sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added if DAS28(CRP) >3.2 after three months. Efficacy was assessed by DAS28(CRP), CDAI, SDAI and ACR/EULAR Boolean remission criteria. Primary analysis was by ITT with last observation carried forward. Completer analysis and ITT without imputations gave similar results (not shown). Values are medians (5%/95% percentiles) or percentage. We used Mann-Whitney or Pearson’s chi-square tests. Results Baseline characteristics were similar between MTX+PLA/MTX+ADA groups: Women: 69%/63%; age: 54.4/56.2 years; disease duration: 83/84 days; anti-CCP positive: 70%/60%; IgM-RF positive: 74%/70%; DAS28(CRP): 5.6/5.5; HAQ: 1.0/1.1 (all NS). Triple therapy was added in 25/17 patients (p=0.25). Treatment target was reached in 46%/58% (MTX+PLA/MTX+ADA) at 1 month, 63%/73% (2 months), 70%/76% (3 months), and 76%/80% (12 months) (NS between groups at all time points). However, in the MTX+ADA group significantly more patients achieved rapid and sustained clinical remission as assessed by DAS28, CDAI, SDAI and ACR/EULAR remission criteria (table). Number needed to treat (NNT) with ADA to achieve remission in one extra patient at 1 year was 4 to 5.9 depending on remission criteria. MTX+PLACEBO MTX+ADALIMUMAB P Number of patients included /completers 91/80 89/81 – Methotrexate (mg/week) 12 months 20 (7/25) 20 (7.5/20) 0.33 Triamcinolone (ml) cumulated 0–12 months 7 (2/17.8) 5.4 (1.8/16.6) 0.084 DAS28(CRP) 1 month 3.4 (1.8–5.9) 2.6 (1.7–5.1) 0.003 DAS28(CRP)≤2.6; 1 month 29% 48% 0.010 ΔDAS28 (CRP) 0–1 month –1.9 (–0.3/–3.8) –2.6 (–0.8/–4.7) 0.0011 DAS28(CRP) 12 months 2.6 (1.7/4.7) 2.0 (1.7/5.2) 0.0088 DAS28(CRP)≤2.6; 12 months 49% 74% 0.0011 CDAI ≤2,8; 12 months 41% 61% 0.011 SDAI ≤3.3; 12 months 40% 63% 0.0028 ACR/EULAR (28 joints) remission; 12 months 31% 48% 0.0241 ACR/EULAR (40 joints) remission; 12 months 27% 47% 0.0098 Conclusions Low disease activity was achieved by

Hand bone loss in early rheumatoid arthritis during a methotrexate-based treat-to-target strategy with or without adalimumab—a substudy of the optimized treatment algorithm in early RA (OPERA) trial

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