Background The relationship between acute phase reactant levels and giant cell arteritis (GCA) disease flares is not known, particularly in the era of interleukin-6 receptor blockade with tocilizumab (TCZ). Prednisone doses at which GCA flares can occur have not been studied thoroughly in prospective clinical trials. Objectives Investigate prednisone doses and acute phase reactant levels at the time of disease flare in patients with GCA. Methods Secondary analyses of prednisone doses, C-reactive protein (CRP) levels, and erythrocyte sedimentation rate (ESR) were performed for patients who experienced GCA flare after achieving remission during 52 weeks of treatment with TCZ-weekly or -every-other-week+26 week prednisone taper (TCZ-QW or TCZ-Q2W) or placebo +26 week or 52 week prednisone taper (PBO+26 or PBO+52). The last CRP and ESR values before first disease flare were used if values on the day of first flare were missing. Analyses are descriptive and were performed post hoc. Results GCA flare after remission was reported in 23% (23/100) of TCZ-QW patients, 26% (13/50) of TCZ-Q2W patients, 68% (34/50) of PBO +26 patients, and 49% (25/51) of PBO +52 patients.1 Median CRP levels and ESR at the time of flare were lower in the TCZ groups than in the PBO groups (Table). In the TCZ groups, 92% (33/36) of flares were associated with normal CRP levels (≤1 mg/dL) and 89% (32/36) were associated with normal ESR values (<30 mm/h). In the PBO groups, 34% (20/59) of flares were associated with normal CRP values and 31% (18/59) with normal ESR. Median (min–max) prednisone doses at the time of disease flare in the combined TCZ and combined PBO groups were 5.5 (0.0–310.0) and 9.0 (0.0–55.0) mg/day, respectively. Among 149 patients in the TCZ groups, 10 (7%) had disease flares while receiving prednisone doses greater than 10 mg/day, accounting for 28% of all disease flares in the TCZ groups. Among 101 patients in the PBO groups, 23 (23%) had disease flares while receiving prednisone doses>10 mg/day, accounting for 39% of all disease flares in the PBO groups. Thus, 33 of the 95 disease flares in GiACTA (35%) occurred while the patient was receiving ≥10 mg/day prednisone. Conclusions Acute phase reactants are not reliable correlates of disease flare in TCZ-treated patients, but approximately one-third of all PBO +prednisone patients also had normal acute phase reactants at the time of disease flare. Median prednisone dose at the time of disease flare for TCZ-treated patients was numerically lower than that of patients treated with PBO +prednisone. One-third of all disease flares in GiACTA occurred while the patient was receiving >10 mg/day prednisone. Reference [1] Stone JH, et al. N Engl J Med2017;377:317–328. Acknowledgements This study was sponsored by F. Hoffmann-La Roche Ltd. Disclosure of Interest J. Stone Grant/research support from: Roche, Genentech, Xencor, Consultant for: Roche, Genentech, Xencor, K. Tuckwell Shareholder of: Roche, Employee of: Genentech, S. Dimonaco Employee of: Roche, M. Klearman Employee of: Genentech, M. Aringer Consultant for: Chugai, Roche, Speakers bureau: Chugai, Roche, D. Blockmans: None declared, E. Brouwer Grant/research support from: Roche, M. C. Cid Consultant for: Roche, Novartis, Boehringer-Ingelheim, B. Dasgupta Consultant for: Roche, GlaxoSmithKline, J. Rech: None declared, C. Salvarani: None declared, H. Schulze-Koops: None declared, G. Schett Grant/research support from: AbbVie, BMS, Celgene, Chugai, GSK, Lilly, Novartis, Roche, Sanofi, UCB, Consultant for: AbbVie, BMS, Celgene, Chugai, GSK, Lilly, Novartis, Roche, Sanofi, UCB, R. Spiera Grant/research support from: Roche/Genentech, Consultant for: Roche/Genentech, S. H. Unizony: None declared, N. Collinson Employee of: Roche

BackgroundTocilizumab (TCZ), a humanised anti–interleukin-6 (IL-6) receptor monoclonal antibody, was recently approved for the treatment of patients with giant cell arteritis (GCA). Evidence was based on results of a double-blind randomised controlled trial (RCT) in GCA patients given 162 mg TCZ either weekly (QW) or every other week (Q2W) via subcutaneous (SC) route (GiACTA trial1). A second RCT conducted using 8 mg/kg TCZ given intravenously (IV) every 4 weeks (Q4W) also showed positive outcomes in GCA patients.2 The double-blind dosing portion of each study lasted approximately 1 year. All three regimens (SC 162 mg QW, SC 162 mg Q2W, IV 8 mg/kg Q4W) resulted in positive outcomes for sustained remission of GCA. However, a higher benefit was noted in some key secondary efficacy outcomes with the QW vs the Q2W SC regimen.1ObjectivesTo characterise the pharmacokinetics (PK) of TCZ in the GCA population and to assess the impact of the exposure differential from the three regimens on pharmacodynamic (PD) markers.MethodsTCZ levels and PD biomarkers (soluble IL-6 receptor [sIL-6R], IL-6, erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]) were measured using validated assays at regular intervals throughout the dosing period from all patients in each trial. A comparison of PK and PD outcomes was conducted to understand the dose exposure–response relationships.ResultsAt week 52, mean trough steady state exposure (Ctrough), a primary PK driver of TCZ efficacy, was highest from SC 162 mg QW, followed by IV 8 mg/kg Q4W, and finally SC Q2W (figure 1). Of the PD end points, at week 52, sIL-6R levels were similar for the SC QW and IV regimens but lower for the SC Q2W regimen (figure 1), possibly demonstrating a higher level of target engagement from the SC QW and IV regimens compared with the Q2W regimen. IL-6 levels increased vs baseline after TCZ administration for all three regimens, reflecting displacement of bound, endogenous IL-6 from its receptor, consistent with the mechanism of action of TCZ. ESR levels decreased to a similar extent in response to TCZ administration with all three regimens. Change from baseline in CRP was comparable between the two SC regimens (~79%–93% reduction from baseline from the QW and Q2W regimens, respectively). Quantitative changes in CRP values are not available for the IV study.ConclusionsComparison of Ctrough after 52 weeks of dosing with TCZ from the 8 mg/kg IV regimen with that obtained from two SC regimens showed that exposures from the IV regimen were within the range of exposures of the QW and Q2W regimens. Comparison of PD outcomes showed that all three regimens had comparable results, with the possible exception of lower levels of sIL-6R (a mechanistic marker reflecting serum concentration and target engagement) from the SC Q2W regimen. Comparability of PD results is consistent with the similar efficacy outcomes seen in the SC and IV trials.References[1] Stone JH, et al. N Engl J Med2017;377:317–328. [2] Villiger PM, et al. Lancet2016;387:1921–1927.AcknowledgementsThis study was sponsored by F. Hoffmann-La Roche Ltd.Disclosure of InterestN. L. Mallalieu Shareholder of: Roche, Employee of: Roche, J. H. Stone Grant/research support from: Roche, Genentech, Xencor, Consultant for: Roche, Genentech, Xencor, P. Villiger: None declared, M. Klearman Employee of: Genentech, L. Brockwell Employee of: Roche, S. Dimonaco Employee of: Roche, J. E. Charion Employee of: Roche

Background The arterial uptake of 18fluorine-2-deoxy-d-glucose (FDG) by positron emission tomography-computed tomography (PET/CT) has been used for the diagnosis of giant cell arteritis (GCA). The role for PET/CT in following disease activity and monitoring treatment effects, however, remains unclear Objectives To examine the degree of FDG uptake within the large arteries of GCA patients after 1 year of treatment Methods We studied a subgroup of patients enrolled in the GiACTA trial.1 Patients received either tocilizumab (TCZ) given weekly or every other week plus a 26 week prednisone taper, or placebo (PBO) plus either a 26- or 52 week prednisone taper. PET/CTs were done according to site feasibility and not as part of the GiACTA protocol. For this analysis, the 2 TCZ and PBO groups, respectively, were combined. Patients had whole-body PET/CT imaging within 16 weeks of week 52 visit. The ascending aorta, carotid artery and subclavian artery territories were assessed by maximum standardised FDG uptake values (mSUV) measurement. For each territory, we calculated average, most diseased segment (MDS) and most diseased slide mSUVs and target background ratios (TBR). PET/CTs were read centrally by investigators blinded to the clinical and treatment data Results From 251 patients enrolled in GiACTA, 24 patients underwent PET/CT within 16 weeks of week 52 visit. Seventeen patients (71%) received TCZ plus a prednisone taper (TCZ group) and 7 patients received a prednisone taper alone (PBO group). There were no significant differences between groups in baseline characteristics (table 1). Mean (SD) cumulative prednisone dose at week 52 was 2.5 g (1.7 g) in the TCZ group and 3.2 g (1.2 g) in the PBO group (p=0.11). FDG uptake was consistently numerically lower in all vascular territories in TCZ-treated patients compared to PBO-treated patients except in the ascending aorta. However, the between-group differences were statistically significant only in the left subclavian artery (table 2). Adjustment for selected confounders (new onset disease, baseline prednisone dose, prednisone dose at the time of PET/CT, cumulative prednisone dose, flare prior to PET/CT and clinical activity at the time of PET/CT) did not alter the conclusions derived from the univariate analyses Table 1 Baseline characteristics All results represent means (SD) except otherwise indicated. PBO=placebo, TCZ=tocilizumab Table 2 Results All results represent means (SD). mSUV=maximum standardised uptake value, MDS=most diseased segment, TBR=target to background ratio Conclusions In this exploratory study, subclavian FGD-uptake was significantly reduced in GCA patients treated with TCZ plus prednisone versus prednisone monotheraphy despite lower cumulative prednisone doses. A larger, carefully designed prospective study is required to fully understand the utility of PET/CT in the longitudinal evaluation of large-vessel vasculitis associated with GCA Reference [1] Stone, et al. N Engl J Med2017. PMID28745999. Disclosure of Interest None declared

Background Few studies have conducted head-to-head comparisons of malignancy risk between different types of biologics in rheumatoid arthritis (RA). Objectives To examine the rate of incident malignancy excluding non-melanoma skin cancer (NMSC) in RA patients newly treated with tocilizumab (TCZ) versus TNF inhibitors (TNFi). Methods We conducted a cohort study using data from 3 U.S. healthcare claims databases (2010–2015) – Medicare, IMS PharMetrics Plus or Truven MarketScan. Adults aged ≥18 years with RA who newly started TCZ or a TNFi after failing a different TNFi, abatacept or tofacitinib were included. The primary outcome was incident malignancy excluding NMSC based on 2 diagnosis codes within 2 months (specificity >98%). The 10 most frequently occurring cancers, leukaemia and human papilloma virus-related cancer and all-cause mortality were analysed as individual secondary endpoints. (table 1). For the primary as-treated analysis, follow-up time started the day after cohort entry and ended on treatment discontinuation, outcome occurrence, disenrollment, death, or the end of study period. To control for >60 potential confounders, TCZ starters were propensity score (PS)-matched to TNFi starters with a variable ratio of 1:3 within each database. Hazard ratios (HR) from the 3 PS-matched cohorts were combined by a fixed-effects model. Results We included a total of 10,393 TCZ initiators PS-matched to 26,357 TNFi initiators. A total of 118 malignancies occurred in TCZ starters and 322 in TNFi starters across the three databases. The IR of malignancy per 100 person-years ranged from 0.81 (IMS) to 2.18 (Medicare) in TCZ and from 0.98 (MarketScan) to 2.16 (Medicare) in TNFi. The risk of incident malignancy was similar between the two groups across all three databases (table 1), with a combined HR of 0.92 (95% CI: 0.74 to 1.14) in TCZ versus TNFi. Secondary analyses by cancer subtype and all-cause mortality showed similar results. Conclusions This large multi-database cohort study found no difference in the risk of malignancy excluding NMSC in patients with RA who newly start TCZ versus TNFi. Disclosure of Interest S. Kim Grant/research support from: Roche, Pfizer, Bristol-Myers Squibb, A. Pawar : None declared, R. Desai: None declared, S. Gale Employee of: Genentech, M. Klearman Employee of: Genentech, K. Sarsour Employee of: Genentech, D. Solomon Grant/research support from: Roche, Pfizer, Lilly, Amgen, CORRONA, S. Schneeweiss Grant/research support from: Genentech/Roche, Boehringer Ingelheim, Consultant for: Aetion, WHISCON, LLC

Background GiACTA, a randomized, double-blind, placebo-controlled trial, evaluated the efficacy and safety of tocilizumab (TCZ), an IL-6 receptor-α inhibitor, in patients with giant cell arteritis (GCA).1,2 Objectives Secondary analyses to evaluate the differential efficacy and safety of TCZ between patients with new-onset and relapsing GCA and to evaluate the TCZ exposure-efficacy relationship at week 52 of the trial. Methods Patients aged ≥50 years with active GCA were randomly assigned 1:1:2:1 to short-course prednisone (PBO+26), long-course prednisone (PBO+52) (26-week or 52-week prednisone taper + weekly subcutaneous [SC] placebo, respectively), weekly (TCZ-QW) or every-other-week (TCZ-Q2W) SC TCZ 162 mg + 26-week prednisone taper. Subgroup analysis was performed by disease-onset status (new-onset vs relapsing) to evaluate the proportions of patients in sustained remission at week 52 and time to flare. The impact of TCZ exposure, categorized into high, medium and low tertiles, on time to flare was evaluated across all patients in all treatment arms. Results Randomization included 251 patients, 119 (47%) with new-onset and 132 (53%) with relapsing GCA, distributed evenly across groups. Higher proportions of patients achieved sustained remission in the TCZ vs placebo groups regardless of disease onset (new-onset, relapsing–TCZ-QW: 59.6%, 52.8%; TCZ-Q2W: 57.7%, 47.8%; PBO+26: 21.7%, 7.4%; PBO+52: 21.7%, 14.3%, respectively). Patients with relapsing disease at baseline were in relapse-free remission longer and thus had lower risk for flare (hazard ratio) when treated with TCZ-QW than TCZ-Q2W. Hazard ratio (99% CI) for flare vs PBO+26 was 0.23 (0.09–0.61) for TCZ-QW and 0.42 (0.14–1.28) for TCZ-Q2W; vs PBO+52 it was 0.36 (0.13–1.00) for TCZ-QW and 0.67 (0.21–2.10) for TCZ-Q2W. TCZ exposure-efficacy analysis showed that most patients in the low exposure tertile had been treated with TCZ-Q2W (80%) whereas those with medium and high exposure primarily received TCZ-QW (84% and 98%, respectively). Kaplan-Meier analysis demonstrated that patients with higher exposure benefited from a longer time to flare (Figure). Adverse events (AEs) were similar across groups. Serious AEs were reported in 15.0% TCZ-QW, 14.3% TCZ-Q2W, 22.0% PBO+26 and 25.5% PBO+52 patients; rates were similar between new-onset and relapsing patients. Conclusions The compelling treatment effect of TCZ in GCA patients as measured by sustained remission to 52 weeks was consistent regardless of disease-onset status. Duration of relapse-free remission until flare was longer in patients with higher TCZ exposure, most notably in relapsing patients treated with TCZ-QW. References Unizony SH et al. Int J Rheumatol. 2013;2013:912562. Stone JH et al. 2016 ACR/ARHP Annual Mtg; Washington, DC; A911. Disclosure of Interest J. Stone Grant/research support from: Roche, Genentech, Xencor, Consultant for: Roche, Genentech, Xencor, K. Tuckwell Shareholder of: Roche, Employee of: Roche, S. Dimonaco Employee of: Roche Products Ltd., M. Klearman Employee of: Genentech, N. Mallalieu Shareholder of: Roche, Employee of: Roche, M. Aringer Speakers bureau: Roche, Chugai, D. Blockmans: None declared, E. Brouwer Consultant for: Roche, M. Cid Speakers bureau: Roche, Novartis, B. Dasgupta Speakers bureau: Roche, GlaxoSmithKline, J. Rech: None declared, C. Salvarani: None declared, G. Schett Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Lilly, Novartis, Roche, Sanofi, UCB, H. Schulze-Koops: None declared, R. Spiera Grant/research support from: Roche, Genentech, Consultant for: Roche, Genentech, S. Unizony: None declared, N. Collinson Employee of: Roche Products Ltd.

Background Classification criteria are often used to standardize the enrollment of patients (pts) in clinical studies. American College of Rheumatology (ACR) classification criteria for giant cell arteritis (GCA)1 are >25 years old. Advances in diagnosis and clinical understanding of GCA make their relevance to current studies questionable. Objectives To compare inclusion criteria for the GiACTA (tocilizumab for GCA) study2 with 1990 ACR GCA classification criteria. Methods Pts were enrolled into GiACTA according to study inclusion criteria and were evaluated as to whether they met the 1990 ACR classification criteria (Table). Data are from a live database. Results Of the 251 pts enrolled into GiACTA, 198 (79%) pts met the 1990 ACR classification criteria. The 53 pts who did not fulfill ACR criteria were eligible for GiACTA based on cross-sectional imaging studies and/or polymyalgia rheumatica (PMR) symptoms. In total, 156 (62%) pts had positive temporal artery biopsies (TAB); of these, 24 also had positive imaging findings. The remaining 95 (38%) pts had no TAB or negative TAB; diagnosis of GCA was confirmed by positive findings from large-vessel imaging studies. Positron emission tomography (PET), often coupled with computed tomography (CT), was important in diagnosis. Positive PET/CT findings contributed to GCA diagnosis in 97 (39%) GiACTA pts. CT angiography and magnetic resonance angiography contributed to diagnosis in 14 (6%) and 8 (3%) pts, respectively. New-onset headache, the only GCA symptom in the ACR criteria, was absent in 33% of GiACTA pts. However, other symptoms that often accompany GCA (PMR, scalp tenderness, jaw claudication, ischemia-related vision loss) were present in 62%, 36%, 34%, and 10% of pts, respectively. GiACTA Entry Criteria for the Classification of GCA ACR Criteria for the Classification of Giant Cell (Temporal) Arteritisa Age ≥50 y Age at disease onset ≥50 y History of ESR ≥50 mm/h (or CRP ≥2.45 mg/dL if ESR unavailable) Elevated ESR ≥50 mm/h At least one of the following: – Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp or temporal artery tenderness or decreased pulsation, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain on mastication)– Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness New-onset headache Temporal artery abnormality (tenderness to palpation or decreased pulsation) At least one of the following: – TAB revealing features of GCA– Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as MRA, CTA, or PET-CT Positive TAB CRP, C-reactive protein; CTA, computed tomography angiography; ESR, erythrocyte sedimentation rate; MRA, magnetic resonance angiography. aThe presence of ≥3 criteria classifies a patient as having GCA. Conclusions The 1990 ACR classification criteria for GCA require updating. Cross-sectional imaging, particularly PET/CT, now plays a major role in establishing the diagnosis of GCA. Symptoms in addition to headache merit consideration as part of revised classification criteria. References Arthritis Rheum 1990;33:1122. Int J Rheumatol 2013;2013:912562. doi: 10.1155/2013/912562. Disclosure of Interest K. Tuckwell Shareholder of: Roche, Employee of: Roche Products Ltd., N. Collinson Shareholder of: Roche, Employee of: Roche Products Ltd., M. Klearman Shareholder of: Roche, Employee of: Genentech, S. Dimonaco Employee of: Roche Products Ltd., J. Stone Grant/research support from: Roche, Genentech, Consultant for: Roche, Genentech

Background GiACTA is a randomized, double-blind, placebo-controlled trial of an interleukin-6 receptor antagonist (tocilizumab [TCZ]) in giant cell arteritis (GCA) (ClinicalTrials.gov NCT01791153). 200 of the target 250 pts have been enrolled; recruitment is ongoing, making it the largest GCA trial to date. The trial hypothesis is that TCZ is effective at achieving sustained, corticosteroid (CS)-free remissions. Objectives To report baseline characteristics of the first 200 pts enrolled and to compare characteristics of pts with new-onset GCA (n=95) to those with relapsing GCA at enrollment (n=105). Methods Major inclusion criteria: age ≥50 y, historical ESR ≥50 mm/h or CRP ≥2.45 mg/dL, unequivocal cranial GCA symptoms or polymyalgia rheumatic (PMR), and positive temporal artery biopsy (TAB) or large-vessel imaging. The trial includes 4 arms: TCZ 162 mg SC QW plus 6-mo prednisone taper; TCZ SC 162 mg Q2W plus 6-mo prednisone taper; prednisone only, 6-mo taper; and prednisone only, 12-mo taper. Selection of the initial prednisone dose (between 20 mg/d and 60 mg/d) is at investigator discretion. The CS taper is blinded at doses <20 mg/d. Data are from a live study database and are subject to change. Results The mean age among pts enrolled thus far is 69 y (range, 53-84); 75% are women. At entry, 95 (48%) had new-onset GCA and 105 (52%) had relapsing disease. Baseline comorbid conditions include hypertension (53%) and diabetes (12%). There have been 2 screen failures for every 5 pts enrolled. The most common reason for screen failure was insufficient evidence to support the protocol-defined diagnosis of GCA. 57% had positive TAB, and 43% were enrolled based on positive cross-sectional imaging studies. 10% had negative TAB but positive imaging study results. PMR symptoms were present in 33% of relapsing pts but only in 10% with new-onset GCA. The percentages with persistent cranial arteritis symptoms at baseline (following prednisone after initial suspicion of GCA) were 34% among new-onset pts and 44% among relapsing pts. The mean daily prednisone dose at entry for pts with new-onset GCA was 40 mg compared with 30 mg for those with relapsing disease. Although 20% of new-onset pts entered on 60 mg/d prednisone, only 4% of those with relapsing disease entered at that dose. Conversely, 36% of relapsing pts entered at the minimum daily prednisone dose – 20 mg/d – but only 12% of those with new-onset disease entered at that dose. The mean baseline BMI for pts with relapsing disease (n=102) was slightly higher than that of new-onset pts (n=92): 26.7±5.3 vs 25.1±3.9. At the time of this analysis, 54 pts (24 new onset, 30 relapsing) had received escape prednisone for disease flares. Conclusions Demographic features of the GiACTA population reflect the characteristic epidemiologic profile of GCA. A substantial proportion of pts were enrolled based on large-vessel imaging findings rather than positive TAB. Pts with relapsing disease at entry may be more likely to have PMR at baseline and to enter at lower prednisone doses yet have higher baseline BMIs. This is likely a result of previous CS treatment. More than 25% of pts enrolled to date have received escape therapy. Therefore, if TCZ is effective as a steroid-sparing agent in GCA, the trial protocol under conduct now should have a robust ability to prove this hypothesis. Disclosure of Interest K. Tuckwell Employee of: Roche, N. Collinson Employee of: Roche, M. Klearman Shareholder of: Roche, Employee of: Genentech, S. Dimonaco Employee of: Roche, J. Stone Grant/research support from: Roche

Background Insulin resistance is increased in rheumatoid arthritis (RA). Reductions in inflammation, glucocorticoid therapy and disease-modifying anti-rheumatic drugs (DMARDs) have been associated with improvement in insulin resistance in patients with RA. Objectives To study whether tocilizumab (TCZ) therapy, an IL-6 receptor-inhibiting monoclonal antibody, improves insulin resistance in patients with RA. Methods TOWARD was a phase 3 study in patients with moderate to severe active RA on stable oral DMARDs that compared TCZ 8 mg/kg to placebo with 2:1 randomisation. Insulin resistance was calculated using the homeostatic model (HOMA-IR). Insulin resistance was classified as a HOMA-IR ≥2.2. Associations of baseline HOMA-IR against variables were analysed using linear regression. We examined associations between baseline HOMA-IR and baseline demographics, cardiovascular disease risk factors and disease-related factors using linear regression. Associations between change in HOMA-IR and change in RA disease parameters were also analysed using regression. Results Of the 1123 patients in the study, HOMA-IR could be calculated in 893 (79.5%). Median (IQR) age, glucose, insulin and HOMA-IR were 54 (46-62) years, 5.1 (4.6-5.6) mmol/l, 7.6 (4.6-12.6) µU/ml and 1.7 (1.0-2.9), respectively. 328 patients (37%) had insulin resistance. In an age- and gender-adjusted analysis, baseline HOMA-IR was associated with older age, higher BMI, SBP and DBP as well as IL-6 level (β-coefficient [95% CI]; 0.01 [0.01, 0.02] per pg/dl), RF positivity (0.25 [0.12, 0.38]) and lower IL-6 receptor levels (–0.02 [–0.02,–0.01] per ng/dl). HOMA-IR was reduced over 24 weeks in patients with insulin resistance who received TCZ but not in those who received placebo (Table). Image/graph Conclusions Insulin resistance is common in RA patients with inadequate response to DMARDs and is associated with RF positivity and IL-6 levels. In patients with pre-existing insulin resistance, HOMA-IR was significantly improved by TCZ therapy while unchanged by placebo. Understanding the mechanistic links between IL-6 and insulin regulation may provide an additional rationale for a stratified approach to using biologics to reduce cardiovascular disease risk in patients with RA. Disclosure of Interest H. Mirjafari Employee of: Roche Products Ltd, J. Wang Employee of: Roche Products Ltd, M. Klearman Employee of: Genentech, a member of the Roche group, O. Harari Employee of: Roche, I. Bruce Grant/research support from: UCB, Roche, GSK, Genzyme/Sanofi, Consultant for: Pfizer, UCB, GSK, Human Genome Sciences, Roche, Paid instructor for: Pfizer, UCB, GSK, Human Genome Sciences, Roche, Speakers bureau: Pfizer, UCB, GSK, Human Genome Sciences, Roche

Background Clinical and epidemiological evidence implicates elevated lipoprotein (a) [Lp(a)] level as a risk factor for cardiovascular disease (CVD).1 Lp(a) is also implicated as a causal agent in the atherothrombotic process.1 RA pts are at increased risk for CVD and have higher Lp(a) levels than the general population.2 Treatment guidelines recommend reduction of Lp(a) at levels >50 mg/dL.3 Niacin is the most recognized means to lower Lp(a) but is no longer recommended given recent trial results.4 Although some evidence implies a beneficial role for TNF inhibitors in reducing CV risk and mortality in RA pts, their effect on Lp(a) remains unclear. Some studies report a decrease in Lp(a) following treatment with MTX and TNF inhibitors; others show no such effects.5–7 Interleukin-6 (IL-6), a proinflammatory cytokine, has been shown to increase Lp(a) levels in monkey hepatocyte cultures.8 Conversely, inhibition of IL-6 signaling with TCZ decreases serum Lp(a) levels.9,10 Objectives This post hoc analysis examined the response of Lp(a) to TCZ in comparison to ADA and to MTX in two separate clinical trials. Methods ADACTA was a randomized, double-blind, phase 4 study in RA pts (TCZ, n=163; ADA, n=163).11 Pts received TCZ 8 mg/kg IV Q4W or ADA 40 mg SC Q2W for 24 wks, both as monotherapy. MEASURE was a randomized, double-blind, phase 3 study in RA pts (TCZ + MTX, n=69; pbo + MTX, n=63).10 Pts received TCZ 8 mg/kg IV Q4W or pbo IV Q4W, both in combination with MTX. Serum samples were analyzed at baseline (BL) and wk 8 for Lp(a). Change from BL to wk 8 in Lp(a) was summarized within each study split by EULAR and ACR50 response at wk 24. Shifts from >50 mg/dL to ≤50 mg/dL in Lp(a) from BL to wk 8 were summarized for each study. Results A greater reduction in Lp(a) was seen in pts receiving TCZ compared to those receiving ADA (p<0.0001) and in pts receiving TCZ + MTX compared to those receiving MTX (p<0.0001) (Table 1). Although the reduction was greater in both ACR50 and EULAR responders compared to nonresponders, the numerical differences were mostly small. At wk 8, numerically higher proportions of pts with BL Lp(a) >50 mg/dL improved (defined as achieving Lp(a) ≤50 mg/dL) in the TCZ group (11/21 [52.4%]) compared to the ADA group (6/24 [25%]) and in the TCZ + MTX group (7/12 [58.3%]) compared to the MTX group (2/20 [10%]). Conclusions The current analysis showed greater reduction of Lp(a) levels in RA pts treated with TCZ monotherapy compared to ADA and with TCZ + MTX compared to MTX. This effect appears to be partially related to treatment response. These results suggest that IL-6 receptor inhibition may modulate Lp(a) more than MTX or TNF blockade with ADA. More studies are needed to elucidate the hierarchy of signaling pathways that modulate Lp(a) and how this may impact CV risk. References Curr Atheroscler Rep 2013;15:360. Circulation 2003;108:2957. Eur Heart J 2010;31:2844. N Engl J Med 2011;365:2255. Ann NY Acad Sci 2006;1069:414. Arthritis Rheum 2007;56:831. Clin Exp Rheum 2013;31:415-21. Arterioscler Thromb Vasc Biol 1998;18:984. PLoS One 2010;5:e14328. Ann Rheum Dis 2013 doi:10.1136. Lancet 2013;381:1541. Disclosure of Interest C. Gabay Grant/research support: Roche, AbbVie, Merck, Consultant for: Roche, AbbVie, Merck, I. McInnes Grant/research support: Pfizer, Roche, Consultant for: BMS, Pfizer, NovoNordisk, AstraZeneca, Eli Lilly, UCB, Speakers bureau: BMS, Pfizer, NovoNordisk, AstraZeneca, Eli Lilly, UCB, A. Kavanaugh Grant/research support: Roche/Genentech, K. Tuckwell Employee of: Roche, N. Collinson Employee of: Roche, M. Klearman Shareholder of: Roche/Genentech, Employee of: Roche/Genentech, J. Green Employee of: Roche, N. Sattar Consultant for: Roche, Speakers bureau: Roche DOI 10.1136/annrheumdis-2014-eular.3030

Background TCZ is an IL-6-receptor signalling inhibitor licensed for use in RA. Because TCZ may impact how IL-6 affects T-cell activation and B-cell differentiation, response of TCZ-treated pts to vaccination is of interest. Data from small studies suggest TCZ does not negatively affect response to vaccination; more data are needed. Objectives To evaluate effects of TCZ on response to 23-valent pneumococcal polysaccharide vaccine (23VPPV) and tetanus toxoid vaccine (TTV) in RA pts on MTX. Methods This is a preliminary analysis from VISARA, an ongoing, controlled, open-label study in RA pts who have inadequate response/intolerance to ≥1 anti-TNF agent. Pts were stratified by age and randomised (2:1) to TCZ 8 mg/kg IV every 4 wks + MTX (Active) or MTX only (Control) for 20 wks. Baseline (BL) serology samples were collected 3 wks after the first infusion, just before vaccination with 23VPPV and TTV. At 8 wks, anti-pneumococcal and anti-tetanus antibody titres were evaluated. Endpoints were proportion of pts with positive response (2-fold or >1 mg/L increase in serum antibody titres) to ≥6 of 12 23VPPV serotypes (Primary) and proportion with positive response (4-fold or ≥0.2 mg/L increase in serum antibody titres) to TTV (Secondary) at 5 wks post-vaccination. Results For this preliminary analysis, data are available for the first 74/91 enrolled pts and presented only for 61 pts who met the per-protocol criteria (i.e. received ≥1 dose of study medication and both vaccines, had available BL and 8-wk titre samples; no protocol violations). A numerically greater percentage of Control than Active pts responded to ≥6 of 12 23VPPV serotypes at wk 8 (65.0% [95% CI, 44.1-85.9%] vs 53.7% [95% CI, 38.4-68.9%]). Greater proportion of Control than Active pts responded to serotype combinations (from ≥1 to ≥12). However, there was a notable degree of variability between pts as reflected by wide CIs within both groups, particularly for the higher number of serotype combinations (graph). The percentage of responders to TTV was comparable between groups (Active [43.9%; 95% CI, 28.7-59.1%] vs Control [36.8%; 95% CI, 15.2-58.5%]). Conclusions Results suggest TCZ- and MTX-treated RA pts have comparable recall response to TTV, but response to 23VPPV is slightly reduced with TCZ. If possible, pneumococcal polysaccharide vaccination should be given before initiating TCZ to maximise response. These data are for 2 TCZ infusions and may only reflect initial effects of TCZ on the humoural immune response. Effects of long-term dosing are not addressed. Disclosure of Interest C. Bingham III Grant/Research support from: Roche/Genentech, Consultant for: Roche/Genentech, W. Rizzo Grant/Research support from: Advanced Arthritis Care and Research, Consultant for: UCB, Savient, Speakers Bureau: Amgen, Takeda, UCB, Roche, Abbott, M. Klearman Employee of: Roche/Genentech, A. Hassanali Employee of: Roche/Genentech, R. Upmanyu Employee of: Roche, A. Kivitz Speakers Bureau: Roche

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-square. Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-square.

Background RA pts treated with TCZ showed superior clinical benefit vs pts treated with ADA in the ADACTA study1; however, it is unclear whether distinct RA subpopulations responded preferentially to anti-IL6R vs anti-TNFα therapy. Objectives To evaluate biomarker-defined pt subpopulations and their response to TCZ and ADA monotherapy. Methods ADACTA was a randomised, double-blind, 24-wk study in pts with RA of ≥6-mo duration and DAS28 >5.1 who were MTX intolerant or for whom continued treatment with MTX was considered ineffective or inappropriate. Pts received TCZ 8 mg/kg IV every 4 wks (+ placebo [PBO] ADA) or ADA 40 mg SC every 2 wks (+ PBO TCZ) for 24 wks as monotherapy. Serum biomarkers previously identified in TCZ or ADA studies—including CXCL13, CXCL10, CCL2, CCL13, IL8, IL6, IL2, IL10, TNFα, IFNγ, GM-CSF, IL12p70, IL1β, sICAM1, sCD25, MMP1, MMP3 and MMP9—were measured using quantitative immunoassay methods. Baseline (BL) levels (wk 0, n=203) were assessed against ACR20/50/70 response and ΔDAS28-ESR at wk 24 using local regression. Biomarkers were determined to enrich for clinical response if both efficacy endpoints showed improvement. Post-dose changes were assessed at wks 4 and 24 for biomarkers demonstrating enrichment for response. Statistical assessment for post-dose changes was performed using the Wilcoxon rank sum test comparing absolute biomarker levels at wk 0 vs 24, without correction for multiple comparisons. Post-dose changes vs efficacy compared wk 24 levels in ACR50 responders [R] vs non-responders [NR], except sICAM1 wk 4 as indicated. Results Analysis of BL biomarker levels vs efficacy at wk 24 revealed that pts with BL levels above the median for MMP3, CXCL13 or CXCL10 had increased ACR50 response rates and decreased DAS28-ESR scores after TCZ treatment vs pts with BL levels below the median; higher BL levels of these biomarkers did not enrich for ADA response (Table). Conversely, BL levels above the median for sICAM1 were associated with enhanced ADA but not TCZ clinical response. TCZ reduced post-dose levels of MMP3 in all comers (wk 0 vs 24, p<0.0001), while levels decreased with ADA, mainly in ACR50 responders (R vs NR, p<0.05). Reduced CXCL13 levels were observed in all comers with either TCZ (wk 0 vs 24, p<0.0001) or ADA (wk 0 vs 24, p<0.0001), but the CXCL13 decrease correlated with ACR50 response only with ADA (R vs NR, p<0.05). CXCL10 also decreased with ACR50 response only with ADA (R vs NR, p<0.05), though BL CXCL10 levels enriched for TCZ response. Circulating sICAM1 levels decreased with efficacy with TCZ (R vs NR, wk 4, p<0.05), while BL levels enriched for ADA clinical response. Image/graph Conclusions Distinct patterns of biomarkers enriching for response suggest that TCZ and ADA may preferentially demonstrate efficacy in different subpopulations of RA pts. Higher BL levels of distinct biomarkers (MMP3, CXCL13 or CXCL10 for TCZ; sICAM1 for ADA) may enrich for clinical response. Furthermore, post-dose data suggest BL biomarker levels may enrich for efficacy independently of modulation by treatment. References Gabay C et al. Lancet. In press Disclosure of Interest A. Herman Employee of: Genentech, a member of the Roche group, D. Musselman Employee of: Genentech, a member of the Roche group, S. Fischer Employee of: Genentech, a member of the Roche group, A. Setiadi Employee of: Genentech, a member of the Roche group, C. Gabay Grant/research support from: Roche, Consultant for: Roche, Abbvie, Pfizer, UCB, BMS, MSD, A. Kavanaugh Grant/research support from: Roche, Abbott, Amgen, UCB, BMS, Pfizer, Janssen, M. Klearman Employee of: Genentech, a member of the Roche group, A. Song Shareholder of: Roche, Employee of: Genentech, a member of the Roche group, M. Townsend Shareholder of: Genentech, a member of the Roche group, Employee of: Genentech, a member of the Roche group

BackgroundApproximately 1/3 of RA patients (pts) on biologics receive them as monotherapy (without other DMARDs) [1,2]. TCZ, an inhibitor of IL-6 receptor signalling, has been studied as monotherapy in 3 clinical trials [3–5], but direct comparison with an anti-TNF agent has not previously been performed.ObjectivesTo evaluate efficacy and safety of TCZ vs the anti-TNF agent ADA, both given as monotherapy, in RA pts with DAS28 >5.1.MethodsADACTA was a multicentre, randomised, double-blind, 24-wk study designed specifically to test superiority in pts with RA of ≥6-mo duration who were MTX intolerant or for whom continued treatment with MTX was inappropriate. Pts were randomly assigned (1:1) to TCZ 8 mg/kg IV every 4 wks (+ placebo ADA) or ADA 40 mg subcutaneously (SC) every 2 wks (+ placebo TCZ) for 24 wks. Escape to wkly SC ADA/placebo was permitted at wk 16; 10 ADA and 7 TCZ pts escaped. The primary endpoint was mean change from baseline (BL) in DAS28 at 24 wks.ResultsThe intent-to-treat population included 325 pts (163 TCZ, 162 ADA). BL characteristics were similar between the TCZ and ADA arms: mean age 54.4 and 53.3 y, mean RA duration 7.3 and 6.3 y and mean DAS28 6.72 and 6.76, respectively. Efficacy at wk 24: mean change from BL in DAS28 was significantly greater with TCZ (–3.3) than with ADA (–1.8) (Table). A numerical difference between the 2 arms in swollen and tender joint counts, ESR and patient global assessment in favour of TCZ was seen from wk 8 onward. Statistical significance was also achieved in favour of TCZ for DAS28 remission and low disease activity (LDA), and ACR20/50/70 responses (Table). Safety: the incidence of adverse events (AEs) was similar between groups (TCZ: 82.1%; ADA: 82.7%). Serious AEs and serious infections also were similar (TCZ: 11.7%, 3.1%; ADA: 9.9%, 3.1%). Changes in laboratory values, including transaminase and LDL elevations and neutrophil reductions, occurred in both arms, with the proportion of pts with abnormal values higher in the TCZ arm. There were 2 deaths, both in the TCZ arm: 1 from sudden death, the other from reported illicit drug overdose.ConclusionsMonotherapy with TCZ was superior to monotherapy with ADA in reducing signs and symptoms of RA in MTX-intolerant pts or pts for whom MTX treatment was considered ineffective or inappropriate. The overall safety profile of both medications was consistent with previously reported data.ReferencesYazici, Bull NYU Hosp Jt Dis 2008;66:77. Soliman, Ann Rheum Dis 2011;70:583. Dougados Arthritis Rheum 2011 63(Suppl):S1032. Weinblatt Arthritis Rheum 2011 63(Suppl):S864. Jones Ann Rheum Dis 2010;69:88.Disclosure of InterestC. Gabay Consultant for: Roche, Abbott, Merck, UCB, Pfizer, BMS, Merckserono, Novartis, Amgen, Speakers Bureau: Roche, Abbott, Merck, UCB, Pfizer, BMS, Merckserono, Novartis, Amgen, P. Emery Consultant for: Merck, Abbott, Pfizer, Roche, UCB, BMS, R. van Vollenhoven Grant/Research support from: Abbott, GSK, MSD, Pfizer, Roche, UCB, Consultant for: Abbott, GSK, MSD, Pfizer, Roche, UCB, A. Dikranian Speakers Bureau: Genentech, UCB, Abbott, BMS, R. Alten Grant/Research support from: BMS, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, BMS, Novartis, Pfizer, Roche, UCB, Speakers Bureau: Abbott, BMS, Novartis, Pfizer, Roche, UCB, M. Klearman Employee of: Genentech, a member of the Roche group, D. Musselman Employee of: Genentech, a member of the Roche group, S. Agarwal Shareholder of: Genentech, a member of the Roche group, Employee of: Genentech, a member of the Roche group, J. Green Shareholder of: Roche, Employee of: Roche, A. Kavanaugh Grant/Research support from: Roche, Amgen, Abbott, BMS, Janssen, UCB, Pfizer

We have previously reported the complete sequence of the cDNAs corresponding to the alleles at the polymorphic loci (DRB1, DRB3, DQA1, DQB1) of the DRw11 (5) cell line Swei. We now report the nucleotide and derived amino acid sequence of the alleles at the remaining two polymorphic loci, DPA1 and DPB1, from Swei, which types as DPw4b. Comparison of the DPw4bα sequence with previous DPα sequences indicates that it is identical to the DPα chains of DPw4 and DPw2. However, the DPw4bα cDNA encodes a unique 3′ untranslated region that corresponds to sequences contained within the last intron of the DPα genomic gene. These results indicate that alternative splicing occurs within the Swei DPα RNA. Comparison of the DPw4bβ sequence with previously reported DPβ sequences indicates that the first domain is identical to the sequence of the DPβ chain derived from the Burkhardt (Burk) cell line, but that the second domain differs by two amino acids. In addition, a single amino acid difference from DPw2 at position 69 in the first domain of the DPw4bβ chain suggests that this residue is important in determining DP specificity. Furthermore, comparison with other DPβ DNA sequences suggests that variable regions occur at positions 8–11, 55–57, and 84–87.

The HLA-D region is composed of three subregions termed DR, DQ, and DP. We previously reported the sequence of a DR5 beta I and two DR5 beta III cDNA from the DR5 cell line Swei. We now report on the nucleotide and deduced amino acid sequence of the DQ alpha and DQ beta cDNA from the same DR5 cell line, which also types as DQw3. Comparison with other available DQ sequences indicates that DQ alpha has one region of major variability, whereas DQ beta appears to have four regions of variability. In addition, these comparisons indicate that DQw3 alpha from DR5 is different from DQw3 alpha from DR4, but identical to DQw2 alpha from DR3. In contrast, DQw3 beta from DR5 is very similar to DQw3 beta from DR4. These data indicate that at least for DQw2 and DQw3 it is the DQ beta chain that is responsible for DQ typing. Most sequence differences in DQ alleles can be attributed to point mutations; however, codon additions/deletions in the DQ alpha chain may contribute to variability. In addition, regions of possible gene conversion in the DQ alpha and DQ beta chains is suggested by the presence of a chi-like sequence in each chain. Finally, comparison of available haplotypes suggest recombination events may take place between DQ beta and DQ alpha, between DQ alpha and DR beta I, and between DR beta I and DR beta III.

The binding of the beta subunit of Nerve Growth Factor (beta NGF) to membrane preparations of 8-day chick embryo dorsal root ganglia (DRG) has been investigated under conditions similar to those used to study the binding of beta NGF to intact single cell dissociates of DRG. The equilibrium binding data reveal heterogeneityy of binding that is more complex than that seen with intact cells. Binding is not saturable up to 125I beta NGF concentrations of 10(-8) M. Steady-state and kinetic binding data show two sites with dissociation constants similar to those found on DRG cells. In addition, displacement data reveal a binding component with lower affinity (Kd = 10(-6) M) which is not found on intact cells. As with intact cells, the difference in the affinities of the two high affinity sites has been shown to be due to different rate constants of dissociation. The kinetics of dissociation of NGF are slower with membranes than with cells, and dissociation characteristics of 125I beta NGF change with increasing time of exposure to membranes. Degradation of 125I beta NGF during incubation with membranes is minimal and does not complicate the analysis of steady-state binding. Insulin does not bind to either of the two high affinity sites. Heterogeneity of the 125I beta NGF preparation and cooperativity of binding as a cause for the heterogeneity of the binding of NGF has been ruled out. Although there was an apparent increase in the rate of dissociation of 125I beta NGF in the presence of unlabelled NGF, a finding previously interpreted as evidence for negative cooperativity, this was shown to be independent of receptor site occupancy by NGF, and in part due to isotopic dilution within a diffusion barrier around the membranes.