Daryl K. MacCarter

Changes in Ultrasonographic Vascularity Upon Initiation of Adalimumab Combination Therapy in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate.

To assess joint disease activity by ultrasound (US) in patients with rheumatoid arthritis (RA) initiating treatment with adalimumab (ADA) plus methotrexate (MTX).

FRI0238 Changes in Ultrasonographic Vascularity upon Initiation of Adalimumab Combination Therapy in Rheumatoid Arthritis Patients with Inadequate Response to Methotrexate

Background Control of disease activity in patients with rheumatoid arthritis (RA) has become achievable using synthetic and biologic disease modifying anti-rheumatic drugs, both as monotherapy or in combination. However, residual inflammatory disease can be revealed by sensitive imaging techniques such as ultrasonography in patients with remission of disease activity. Objectives To evaluate ultrasonographic vascularity changes in the joints of RA patients with previous methotrexate (MTX) inadequate-response upon initiation of adalimumab (ADA) combination therapy with two different doses of MTX. Methods MUSICA was a double-blind, randomized, controlled trial evaluating the efficacy of 2 different dosages of MTX (7.5 or 20 mg/wk) in combination with ADA (40 mg every other wk) for 24 wks in RA patients with previous inadequate response to MTX. Dorsal and volar Power Doppler (PD) images of bilateral metacarpophalangeal (MCP) joints 2, 3, 5, and dorsal images alone of metatarsophalangeal joint 5 (MTP5) and wrists were scored by 2 of 4 independent ultrasound-experienced rheumatologists using a semi-quantitative 4-grade scale. Patients with baseline and wk-24 ultrasonographic images were subgrouped based on 28-joint count disease activity score using C-reactive protein (DAS28[CRP] <2.6, 2.6<3.2, 3.2<5.1, ≥5.1) to compare wk-24 mean vascularity scores and change from baseline. Results After 24-wk treatment of ADA with 7.5 or 20 mg/wk MTX, rapid decreases in mean synovial vascularity were observed regardless of achievement of disease control, with most improvement occurring within the first 4 wks. The wrist had the most baseline PD activity, 1.6 out of 6. Improvements in vascularity were greatest in MCP2 (-0.5), MCP3 (-0.4), and wrist (-0.4) after 24 wks of ADA + MTX treatment. Dorsal and volar PD vascularity incidence and activity were similar in MCP2, but differed in MCP3 and MCP5 where dorsal imaging encompassed most activity. After 24 wks of ADA + MTX, mean vascularity of the bilateral 5-joint composite score was lowest in patients that achieved DAS28 (CRP) <2.6 (Table), although confidence intervals overlapped with each subgroup. Similarly, a bilateral 3-joint composite score using MCP2, MCP3, and wrist showed lower vascularity scores associated with achievement of lower disease activity. Vascularity for the 5-joint and 3-joint composite scores was not necessarily correlated with improvements in other disease characteristics. Differences comparing MTX treatment groups were minimal whether examining individual joints, 3-, or 5-joint composite scores. Conclusions Upon initiating ADA in MTX inadequate-responders, rapid reduction in joint vascularity was observed in many patients, regardless of MTX dose. Low overall baseline ultrasonographic vascularity values may have partially reflected suppression of inflammation due to prior MTX treatment. Improvements in vascularity in patients were observed irrespective of achieving low disease activity or remission with a numeric trend for lower mean vascularity in patients achieving lower disease activity. Acknowledgements AbbVie sponsored the study (NCT01185288), contributed to its design, participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. Statistical support was provided by Shufang Liu, Ph.D., of AbbVie. Medical writing support was provided by Douglas E. Dylla, Ph.D., of AbbVie. Disclosure of Interest G. Kaeley Consultant for: AbbVie, M. Nishio Speakers bureau: AbbVie, J. Goyal Consultant for: AbbVie, D. MacCarter Consultant for: AbbVie, Speakers bureau: AbbVie, A. Wells Consultant for: AbbVie, A. Cardoso Shareholder of: AbbVie, Employee of: AbbVie, S. Chen Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie DOI 10.1136/annrheumdis-2014-eular.1389

Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab

Background Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. Methods Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. Results In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. Conclusion In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%–1.3% of patients. Trial registration number MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

Clinical Responses and Synovial Vascularity in Obese Rheumatoid Arthritis Patients Treated with Adalimumab and Methotrexate

Objective. Obese patients with rheumatoid arthritis (RA) report more joint swelling and tenderness and often have poorer responses to therapy than nonobese patients. The aim of this posthoc analysis of the MUSICA trial was to compare imaging and clinical disease activity measures in obese and nonobese patients with RA. Methods. MUSICA evaluated methotrexate (MTX) 20 mg/week versus 7.5 mg/week in combination with adalimumab (ADA) in RA patients with an inadequate response to MTX. Patients were categorized by baseline body mass index as normal (< 25), overweight (≥ 25 to < 30), or obese (≥ 30). Synovial vascularity and hypertrophy, swollen and tender joint counts (SJC and TJC), American College of Rheumatology (ACR) responses, and low disease activity (LDA), defined as Clinical Disease Activity Index < 10 and 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP) < 3.2, were assessed at weeks 12 and 24. Results. Patient characteristics were similar among groups at baseline. Obese patients had numerically smaller changes from baseline to weeks 12/24 in SJC, TJC, DAS28-CRP, and synovial hypertrophy and vascularity versus nonobese patients. Significantly fewer obese patients reached ACR20/50 at weeks 12 and 24, and LDA at Week 12; this difference was especially apparent in patients receiving 7.5 mg/week MTX but was no longer significant at Week 24. Conclusion. Obese patients with RA had worse clinical and ultrasonographic responses than nonobese patients, which were partly overcome with time. Obese patients may experience better and faster clinical improvements if ADA is initiated with high-dose (20 mg/week) rather than low-dose MTX. [ClinicalTrials.gov: NCT01185288]

Identification of calcium pyrophosphate deposition disease (CPPD) by ultrasound: reliability of the OMERACT definitions in an extended set of joints—an international multiobserver study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force

Objectives To assess the reliability of the OMERACT ultrasound (US) definitions for the identification of calcium pyrophosphate deposition disease (CPPD) at the metacarpal-phalangeal, triangular fibrocartilage of the wrist (TFC), acromioclavicular (AC) and hip joints. Methods A web-based exercise and subsequent patient-based exercise were carried out. A panel of 30 OMERACT members, participated at the web-based exercise by evaluating twice a set of US images for the presence/absence of CPPD. Afterwards, 19 members of the panel met in Siena, Italy, for the patient-based exercise. During the exercise, all sonographers examined twice eight patients for the presence/absence of CPPD at the same joints. Intraoberserver and interobserver kappa values were calculated for both exercises. Results The web-based exercise yielded high kappa values both in intraobserver and interobserver evaluation for all sites, while in the patient-based exercise, inter-reader agreement was acceptable for the TFC and the AC. TFC reached high interobserver and intraobserver k values in both exercises, ranging from 0.75 to 0.87 (good to excellent agreement). AC reached moderate kappa values, from 0.51 to 0.85 (moderate to excellent agreement) and can readily be used for US CPPD identification. Conclusions Based on the results of our exercise, the OMERACT US definitions for the identification of CPPD demonstrated to be reliable when applied to the TFC and AC. Other sites reached good kappa values in the web-based exercise but failed to achieve good reproducibility at the patient-based exercise, meaning the scanning method must be further refined.

SAT0631 Inter-observer and intra-observer reliability of the omeract ultrasonographic (US) criteria for the diagnosis of calcium pyrophosphate deposition disease (CPPD) at the metacarpal-phalangeal (MCP), wrist, acromion-clavicular (AC) and hip joints

Background The OMERACT US subtask force “US in CPPD” recently created the definitions for US identification of crystal deposits in joints and tested the reliability at the knee [1]. Objectives To assess the inter/intra-observer reliability of US on detecting CPPD at triangular fibrocartilage complex (TFCC) of the wrists, fibrocartilage of the AC joint, hip labrum (HL), hyaline cartilage (HC) of the metacarpal (MC) and femoral head. Methods The OMERACT criteria for CPPD were used for the exercise [1] using a 2 steps approach. First, the panel of experts gave a dichotomous score (presence/absence of CPPD) of 120 images of the sites included, using a web platform. The images were evaluated twice to assess the inter/intra-observer reliability. Then, the experts met in Siena for a patient based exercise. Bilateral evaluation of TFCC, AC, HL /HC of the hip and HC of the II-III MCP of 8 patients was carried out twice in a day, using a dichotomous score for CPPD. 8 US machines (3 GE, 1 Samsung and 4 Esaote) equipped with high resolution linear probes were used. Results Reliability values of static exercise were high for all sites, demonstrating that definitions were clear. The results of the second step are presented in table 1. On live scanning, the TFCC resulted the most reliable site for CPPD assessment, followed by AC. Other sites demonstrated lower kappa values and thus are not reliable for CPPD assessment. Conclusions TFCC of the wrist is the most reliable site for CPPD. By adding these results to the previous [2], we confirm that the OMERACT definitions for CPPD can be applied reliably at the knee (meniscus and HC), TFCC and AC, usually the most involved sites in CPPD. The next step of the OMERACT subtask force will be to test these findings in a longitudinal observational study. References Filippou G, Scirè CA, Damjanov N et al. Definition and reliability assessment of elementary US findings in CPPD. Results of an international multi-observer study by the OMERACT sub-task force “US in CPPD”. J Rheumatol, in press. Disclosure of Interest None declared

AB0311 Clinical Responses and Synovial Vascularity in Obese Rheumatoid Arthritis Patients Treated with Adalimumab and Methotrexate

Background Obese rheumatoid arthritis (RA) patients (pts) may have higher levels of inflammatory mediators, greater joint swelling and tenderness, and suboptimal response to therapy. Objectives We assessed disease activity and treatment response in obese RA pts, using ultrasonography (US) and clinical measures. Methods This post hoc analysis used observed data from the MUSICA trial1 which evaluated the efficacy of high [20 mg/week (wk)] or low (7.5 mg/wk) doses of methotrexate (MTX) in combination with adalimumab (ADA) for 24 weeks (wks) in RA pts with previous inadequate response to MTX who initiated ADA. Pts were grouped according to body mass index (BMI) at baseline (BL): normal BMI <25; overweight BMI ≥25-<30; obese BMI ≥30. Synovial vascularity and hypertrophy were measured by Power Doppler US and Greyscale respectively, bilaterally, at metacarpophalangeal (MCP) joints 2, 3, 5, metatarsophalangeal joint 5 (MTP5) and wrists. Swollen joint count (SJC) of 66 joints, tender joint count (TJC) of 68 joints, 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP), and numbers of pts reaching American College of Rheumatology (ACR) criteria, Clinical Disease Activity Index [CDAI] low disease activity (LDA,<10), DAS28-CRP low disease activity (LDA; DAS<3.2), were assessed at wks 12 and 24. Results Out of 308 pts at BL, 69 pts (22.4%) had BMI <25,102 pts (33.1%) had BMI ≥25-<30 and 137 pts (44.5%) had BMI ≥30. Disease characteristics and ultrasound disease assessments were similar for the 3 BMI subgroups at BL. At wks 12 and 24, compared with pts in the normal and overweight categories, obese pts tended to have numerically smaller mean changes from BL in SJC66, TJC68, DAS28-CRP, synovial hypertrophy and synovial vascularity (table). Compared to pts in the normal and overweight categories, significantly fewer obese pts reached ACR20/50 at wks 12 and 24. Significantly fewer obese pts reached CDAI LDA and DAS28-CRP LDA at wk 12; this difference was driven by those obese pts receiving low dosage of concomitant MTX (7.5 mg/wk), although by wk 24, the differences were no longer significant. There was low to no correlation between synovial vascularity/hypertrophy and clinical findings of swelling and tenderness. The proportion of pts with synovial vascularity=0 in the 3 BMI subgroups at wks 12 and 24 was not statistically different. Conclusions Among obese RA pts initiating ADA, those on low dosage of concomitant MTX had poorer responses than pts in the normal and overweight categories, as measured clinically and by ultrasound imaging, although this effect was partly overcome by wk 24. Obese RA pts may have an improved clinical benefit if ADA is initiated with high (20 mg/week), rather than low dosage of concomitant MTX. References Kaeley et al. ACR/ARHP 2013 Annual Meeting. Boston, MA, USA Acknowledgement AbbVie: study sponsor, contributed to study design, data collection, analysis, interpretation and writing, reviewing and approval of abstract. Medical writing support: Naina Barretto of AbbVie Disclosure of Interest G. Kaeley Consultant for: AbbVie, V. Ranganath Grant/research support from: Genentech, Pfizer, D. MacCarter Consultant for: AbbVie, Speakers bureau: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie, X. Wang Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie

FRI0077 The Use of Ultrasound to Detect Residual Joint Inflammation in Patients with Rheumatoid Arthritis in Clinical Disease Remission

Background Patients (pts) with rheumatoid arthritis (RA), who achieve clinical disease remission by treatment with disease-modifying agents may have residual joint inflammation and vascularization, which can be detected by Power Doppler (PD) ultrasonography. The aim of this analysis was to evaluate the proportion of RA pts with PD activity, 24 weeks (wks) after the addition of adalimumab (ADA) to methotrexate (MTX). Methods MUSICA (NCT01185288), a 24 wk double-blind, randomized, controlled trial evaluated the efficacy of 2 different dosages of MTX (7.5 or 20 mg/wk) plus ADA (40 mg every other wk) in RA pts with inadequate response to MTX. For this analysis, the MTX dosage groups were combined. Synovial vascularization was assessed by PD US at 10 joints (bilateral dorsal and volar views of metacarpophalangeal joints 2, 3, 5; dorsal images alone of metatarsophalangeal joint 5 and wrists), at baseline (BL), wks 4, 8, 12, 16, 20 and 24. Images were scored by ultrasound-experienced rheumatologists using a semi-quantitative 4-grade scale. Joint swelling was assessed for the same 10 joints (SJC10). Disease activity was assessed by 28-joint count disease activity score using C-reactive protein (DAS28[CRP]) (remission <2.6, LDA <3.2, MDA 3.2- <5.1, HDA ≥5.1), and simplified disease activity index (SDAI) (remission ≤3.3, LDA ≤11, MDA 11-≤26, HDA >26). Pearsons coefficient (ρ) was used to assess correlation between continuous variables. Results After 24 wks of treatment with ADA +MTX, 44/309 pts (14%) were in DAS28(CRP) remission (mean PD score, 3.3); 18/309 (5.8%) pts were in SDAI remission (mean PD score, 2.7). At wk 24, for the 10 joints selected, 30/44 (68%) of pts in DAS28(CRP) remission had positive PD scores, while only 15 pts (34%) had ≥1 swollen joint, and only 6 pts (13.6%) had ≥1 tender joint. Ten out of 18 (55%) pts in SDAI remission had a positive PD score, while none had swollen/tender joints. A poor correlation (ρ<0.2) was observed between PD scores and clinical disease scores such as DAS28, SJC66, SJC28, TJC68, TJC28, CDAI, SDAI, PhGA, PGA-pain and disease duration. There was poor correlation (ρ=0.184) between the change from BL to wk 24 in PD scores, and the change from BL to wk 24 in DAS28(CRP) or SDAI. The corresponding shifts in disease activity, mean PD score and SJC10 scores are presented (Table). Conclusions In agreement with other studies, residual joint inflammation was detected by PD US in pts in clinical remission; therefore ultrasound can offer additional information to that obtained from clinical disease measures. Acknowledgements AbbVie sponsored the study (NCT01185288), contributed to its design, participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. Medical writing support was provided by Naina Barretto, Ph.D., of AbbVie. Disclosure of Interest G. Kaeley Consultant for: AbbVie, M. Nishio Speakers bureau: AbbVie, J. Goyal Consultant for: AbbVie, D. MacCarter Consultant for: AbbVie, Speakers bureau: AbbVie, A. Wells Consultant for: AbbVie, A. Cardoso Employee of: AbbVie, S. Liu Employee of: AbbVie, J. Kalabic Employee of: AbbVie, H. Kupper Employee of: AbbVie

SAT0148 Similar Improvements in Quality of Sleep, Satisfaction with Medication and Sexual Impairment Among Rheumatoid Arthritis Patients Upon Initiation of Adalimumab in Combination with Two Doses of Methotrexate

Background Methotrexate (MTX) is used as monotherapy or in combination with other DMARDs in the treatment of patients (pts) with rheumatoid arthritis (RA). Objectives To evaluate the effects of low and high MTX doses in combination with initiation of ADA on patient-reported outcomes (PROs) in MTX-inadequate responders (MTX-IR) with moderate-to-severe RA. Methods MUSICA (NCT01185288) was a randomized, double-blind, controlled trial evaluating the efficacy of two different dosages of MTX, 7.5 or 20 mg/week (wk) in combination with ADA (40 mg every other wk) for 24 wks in MTX-IR RA pts. Pts entering the study had been receiving ≥15 mg/wk MTX for at least 12 wks. At each study visit, from baseline (BL) to wk 24, the following PROs were recorded: quality of sleep, using the Medical Outcomes Sleep (MOS) Index II; Satisfaction with treatment medication, using the Treatment Satisfaction Questionnaire for Medication (TSQM); and sexual impairment due to RA, using a single question of how much did your RA affect sexual functioning over the past 7 days. Last observation carried forward (LOCF) was used to account for missing values. Results 154 pts were enrolled in the 7.5 mg/wk MTX+ADA arm, and 155 pts in the 20 mg/wk MTX+ADA arm. Both arms were similar for BL demographics (mean age 54.8, 25.2% male), disease characteristics (mean disease duration 5.3 years; mean DAS28(CRP) of 5.8). BL values for MOS, TSQM and sexual impairment were similar. At wk 24 after treatment, improvements were observed in all subdomains of the MOS Sleep Index and the TSQM, and Sexual Impairment due to RA (Table). Except for the MOS Sleep Index-Awakened Short of Breath/headache domain, TQSM-Side effects and TQSM-Convenience, the differences from BL were statistically significant. At wk 24, the difference between the scores for the two treatment groups was not statistically significant for any of the subdomains in the MOS Sleep Index or the subdomains in the TSQM, except for Convenience (p=0.023), which was lower for the 20 mg/wk MTX dosage group. At wk 24 after treatment, the difference between the scores between the two treatment groups was not statistically significant for Sexual Impairment. Conclusions Similar to observations in pts with early RA (1), the addition of ADA to MTX in pts with moderate-severe disease and insufficient MTX response, led to improvements in quality of sleep, and satisfaction with treatment medication after 24 wks. Improvements in sexual impairment were also observed. Improvements in all three PROs were observed regardless of the concomitant MTX dosage. References Burmester et al; ARD 2014; 0:1-8 Acknowledgements AbbVie sponsored the study (NCT01185288), contributed to its design, participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. Statistical support was provided by Peigang Li, PhD, and Shufang Liu, PhD; medical writing support was provided by Naina Barretto, PhD, all of AbbVie. Disclosure of Interest G. Kaeley Consultant for: AbbVie, M. Nishio Speakers bureau: AbbVie, D. MacCarter Consultant for: AbbVie, Speakers bureau: AbbVie, J. Griffith Employee of: AbbVie, V. Garg Employee of: AbbVie, H. Kupper Employee of: AbbVie, J. Kalabic Employee of: AbbVie