High Inflammatory Burden Research Articles

842 Impact of Response and Inflammatory Burden at Start of Maintenance Therapy on Clinical Efficacy of Ustekinumab Dosing Regimen in UC: Week 44 Results From UNIFI

INTRODUCTION: The UNIFI maintenance study was a Phase 3, double-blind, placebo-controlled, randomized-withdrawal study in pts with moderate to severely active ulcerative colitis (UC) who failed conventional or biologic therapy and were in clinical response 8 wks after receiving a single ustekinumab (UST) IV induction dose. In this study, pts were randomized to placebo, UST 90 mg SC q8w or q12w. METHODS: To examine the relative efficacy of the UST 90 mg SC q8w or q12w maintenance regimens, subgroup analyses were performed for outcomes of clinical remission, symptomatic remission, and endoscopic improvement at Wk44 for pts who did and did not achieve these endpoints at the start of maintenance. Analyses of clinical remission and endoscopic improvement at Wk44 based on pre-specified cut-points of the concentrations of inflammatory biomarkers (CRP [≤3 mg/L, >3 mg/L] and fecal calprotectin [≤250 mg/kg, >250 mg/kg]) at maintenance baseline were also conducted. RESULTS: For pts who had achieved clinical remission, symptomatic remission, or endoscopic improvement at maintenance baseline, efficacy of UST q8w and q12w regimens for the respective endpoint at Wk44 was similar (Table 1). By contrast, for pts who did not achieve clinical or symptomatic remission or endoscopic improvement at maintenance baseline, UST q8w demonstrated greater efficacy than UST q12w for that endpoint at Wk44. Pts with low inflammatory burden marked by CRP ≤3 mg/L at maintenance baseline achieved similar efficacy at Week 44 with UST q8w and q12w dosing regimens as measured by clinical remission and endoscopic improvement (Table 1). By contrast, pts with high inflammatory burden, marked by CRP >3 mg/L at maintenance baseline, achieved greater efficacy at Wk44 with UST q8w versus q12w dosing over the endpoints. Generally similar trends were seen in pts with fecal calprotectin measurements for low (≤ 250 mg/kg) and high (>250 mg/kg) inflammatory burden at maintenance baseline. CONCLUSION: Among pts with a clinically meaningful response to a single IV induction dose of UST, maintenance treatment with UST q8w or q12w demonstrated similar efficacy at Wk44. By contrast, the efficacy of UST q8w at Week 44 was greater than the q12w regimen for pts with higher inflammatory burden or who did not achieve clinical or symptomatic remission or endoscopic improvement at Wk8. These data suggest that multiple clinical measures can help inform the decision on the most appropriate maintenance dosing regimen for UST in the treatment of pts with UC.

P2681The impact of modifiable life style risk factors on inflammation in patients with coronary artery disease: modelling a target population for anti-inflammatory treatment

Abstract Introduction Modifiable lifestyle risk factors (modRF) of coronary artery disease (CAD) such as smoking, lack of physical activity (PA) and poor diet are associated with high inflammatory burden. An optimisation of modRF might significantly affect the target population for pharmacological anti-inflammatory treatment (AIT) as determined by a hsCRP ≥2 mg/l. Aim To analyse the influence of modRF on hsCRP in a contemporary CAD cohort and model the effect of modRF optimisation on hsCRP in a target population with high inflammatory burden. Methods We included all patients with angiographically documented CAD from an observational cohort study ongoing since 2015 and excluded patients with recent myocardial infarction, malignancy, infectious disease, and immunosuppressive medication. ModRF were assessed by questionnaire at enrolment. Lack of PA was defined as PA <1.5 h/week and poor diet as ≤12 points of an established Mediterranean diet score (MDS, range 0–28 points). The Kruskall-Wallis Test was used to compare hsCRP levels depending on the number of modRF. We performed univariate and multivariate linear regression with log(hsCRP) as the dependent variable. Based on the latter we recalculated hsCRP for each patient assuming optimisation of individual modRF. Results Of the 1003 patients (mean age 69 years, 72% male) included, 48% (N=479) had a hsCRP ≥2 mg/l. HsCRP increased with the incremental number of modRF (median hsCRP-values for 0–3 modRF: 1.1, 1.6, 2.1, 2.7 mg/l, p<0.001). Univariate and multivariate linear regression showed a significant association between log(hsCRP) and each of PA ≥1.5 h/week, MDS >12, and smoking (Table 1). Recalculation of hsCRP levels identified 21% (N=102/479) of patients with hsCRP ≥2 mg/l who could achieve a hsCRP <2 mg/l assuming optimisation of present modRF. Table 1. Linear regression results Univariate Multivariate exp(β) (95% CI) p-value exp(β) (95% CI) p-value PA ≥1.5 h/week 0.63 (0.54, 0.72) <0.001 0.76 (0.66, 0.88) <0.001 MDS >12 0.74 (0.65, 0.86) <0.001 0.83 (0.73, 0.96) <0.010 Smoking 1.16 (1.01, 1.34) <0.040 1.19 (1.03, 1.36) <0.017 Impact of modifiable lifestyle risk factors on hsCRP in 1003 CAD patients. Multivariate analyses are adjusted for age, sex, diabetes, body mass index and intake of cholesterol lowering drugs. Conclusion Modifiable lifestyle risk factors are independently associated with hsCRP levels in CAD patients. A relevant portion of patients with high inflammatory burden might achieve a hsCRP <2 mg/l by lifestyle changes alone. This should be considered in view of the cost and side-effects of pharmacological AIT and for the design of future intervention studies in this field.

692 Low Levels of Ustekinumab Despite Dose Escalation Is a Risk Factor for Surgery

INTRODUCTION: Ustekinumab is an IL-12/23 inhibitor used for the treatment of Crohn's disease (CD). Previous studies have suggested that dose escalation to every 4-week intervals can be beneficial in patients who do not achieve a clinical response on every 8-week maintenance dosing. However, safety and efficacy is unknown in CD patients escalated to more frequently than every 4-week intervals in patients who continue to have low trough drug levels. METHODS: We performed a retrospective chart review of patients on ustekinumab for CD who had dosing escalation to every two weeks (Q2) due to persistent low drug levels (<5 µg/mL) despite being on q4 weeks (Q4) maintenance dosing and clinically losing response. RESULTS: Out of 200 CD patients on ustekinumab 90 mg subcutaneous (SQ) maintenance in our IBD program, 112 underwent reactive therapeutic drug monitoring for loss of response or incomplete response to therapy. Of the 112 with drug levels, none had anti-drug antibodies, but 80 patients had levels <5 mcg/mL. All 80 patients were frequency escalated to q4 week dosing. Of these, 12 patients continued to have low ustekinumab trough levels at week 4 (<5 mcg/mL) and thus were escalated to Q2 week dosing. Eight of the 12 patients had IV reinduction dosing prior to dose escalation to Q2 frequency. Of the 12 patients, 6 (50%) required surgery for their active Crohn's disease. These patients were on Q2 week dosing for median of 16 weeks (range 1-68) prior to surgery. All 6 (100%) were able to be de-escalate to less frequent dosing after surgery. Two patients that were unable to de-escalate their dosing frequency are planning for surgery in the near future. The remaining four patients were able to de-escalate to Q4 dosing after clinical response. See full details in Table 1. No adverse events unrelated to their Crohn's disease, including infections or other safety markers were noted. CONCLUSION: Low levels of ustekinumab despite escalation of dosing to every 2 weeks may suggest a need for Crohn's disease related surgery. In our study, all patients who underwent surgery were able to de-escalate to lower dosing frequency suggesting that high inflammatory disease burden contributed to the low levels of ustekinumab. Further studies are needed to assess the safety and efficacy of high frequency dosing of ustekinumab.

DUBLIN [Degree of Ulcerative colitis Burden of Luminal Inflammation] Score, a Simple Method to Quantify Inflammatory Burden in Ulcerative Colitis.

Endoscopic scores of local severity do not reflect disease extent, or disease burden. The DUBLIN score is a simple bedside clinical score that estimates inflammatory burden using both disease severity and extent. As the need to personalize therapy for ulcerative colitis [UC] patients increases, a score accurately assessing disease burden will be of great relevance. The aim of this study was to assess the clinical utility of the DUBLIN score by comparing its performance with objective biomarkers. The DUBLIN score was calculated as a product of the Mayo Endoscopic Score [0-3] and disease extent [E1-E3]. Correlation with objective biomarkers was performed in a retrospective 'discovery cohort'. A 'validation cohort was recruited from a single centre, where clinical outcomes, colectomy rate, and biochemical data were collected prospectively. The discovery cohort included 70 patients with UC. The DUBLIN score correlated significantly with faecal calprotectin [FCP] levels [r = 0.394; p < 0.01]. Receiver operating characteristic [ROC] analysis using FCP>50μg/g showed a higher area under the ROC curve [AUC] with the DUBLIN score [AUC = 0.76] than with the Mayo Score [AUC = 0.73]. The validation cohort included 41 patients. Patients with a high inflammatory burden [DUBLIN >3] had higher C-reactive protein and FCP, and lower albumin than patients with a low inflammatory burden. A high DUBLIN score was associated with an increased risk of treatment failure. [hazard ratio 2.98 95%, confidence interval 1.002-8.87; p = 0.049]. The DUBLIN score is a simple measure of inflammatory burden, which correlates with objective inflammatory markers and is associated with clinical outcomes, such as treatment failure. The DUBLIN score has the potential to assist in personalizing therapy for patients with UC.

Peripheral arterial occlusive disease as predictor of high atherosclerotic burden

Atherosclerosis is a disease which affects the whole arterial vascular tree. In particular patients with peripheral arterial occlusive disease (PAOD) often suffer from additional atherosclerotic manifestations in other vascular territories. This has adirect impact on cardiovascular prognosis. Atherosclerosis is an inflammatory disease. A high inflammatory burden is associated with polyvascular atherosclerosis and also with the occurrence of cardiovascular events. Control of cardiovascular risk factors is crucial for the treatment of patients with polyvascular atherosclerosis. In addition, anticoagulation treatment is very important in patients with atherosclerosis. Moreover, exercise training is an important treatment option in PAOD patients not only to improve walking distance but also for multiple additional positive effects. So far the role of anti-inflammatory treatment is not clear and must be further elaborated by future clinical research.

Enthesitis-related arthritis: current perspectives.

In this narrative review, we overview the recent literature on enthesitis-related arthritis (ERA). For the purpose of our review, we searched Scopus for recent articles on this subject from 2013 onward, including some classic older articles for perspective. ERA is a juvenile idiopathic arthritis (JIA) subtype more common in males, associated in a majority with human leucocyte antigen B27. Such children generally present with asymmetric oligoarthritis or polyarthritis, predominantly of lower limb joints, associated with enthesitis or sacroiliitis. While diagnosis remains clinical, ultrasound is being increasingly used to detect subclinical enthesitis and for guiding entheseal site injections. Spine MRI can help detect sacroiliitis, inflammatory spinal changes, and pelvic sites of enthesitis in such patients. The recent juvenile spondyloarthropathy disease activity index recognizes the key clinical features of ERA, viz enthesitis and inflammatory back pain, which other disease activity indices used in JIA did not include. Management includes NSAIDs with physical therapy. Conventional disease-modifying agents like sulfasalazine and methotrexate may be used to minimize duration of NSAID use and in those with high inflammatory burden. In patients refractory to these drugs, biologics such as antitumor necrosis factor alpha agents have proven useful, based on evidences from randomized controlled trials and retrospective registry analyses. Factors predicting a poorer outcome in such children include hip or ankle involvement or restricted spinal mobility. Considering that children with ERA have overall poorer long-term outcomes than other subtypes of JIA, there is a need to further optimize therapeutic strategies for such patients.

Presence of pseudopolyps in ulcerative colitis is associated with a higher risk for treatment escalation.

BackgroundPseudopolyps in ulcerative colitis (UC) are considered as indicators of previous episodes of severe inflammation and ulceration of the mucosa. The aim of the study was to investigate the long-term outcomes of patients treated for UC, with or without pseudopolyps.MethodsThis was a retrospective single-center study. Consecutive patients with UC and available endoscopic data from 2000 until 2016 were eligible for the study and were followed until June 2017. Patients with incomplete medical/endoscopic charts or interrupted follow up were excluded from the study. Primary outcomes included time to treatment escalation, treatment escalation to biological agents or surgery, and UC-related hospitalization.ResultsEighty-three UC patients were included in the study, of whom 25 (30%) had pseudopolyps. The median duration of follow up was 2.8 years (interquartile range: 1.1-4.9). Multiple Cox regression analysis identified the presence of pseudopolyps as the only variable independently associated with treatment escalation (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.2-4.3; P=0.014) and escalation to biological agents or surgery (HR 6.3, 95%CI 1.9-20.7; P=0.002).ConclusionThis retrospective single-center study provides the first preliminary evidence that patients with UC and pseudopolyps may represent a subpopulation with a higher inflammatory burden and a greater need for treatment escalation, including to biological agents or surgery. Large, prospective multicenter studies are certainly warranted to confirm these findings.

Polyarticular evolution and late-onset psoriasis may be associated with cardiovascular disease in psoriatic arthritis.

Patients with psoriatic arthritis (PsA) have high prevalence of cardiovascular risk factors (CVRF), and they also show higher rates of cardiovascular disease (CVD). We aimed to corroborate these findings and identify factors associated with these events in our clinical setting. This cross-sectional study included 340 consecutive patients seen in a tertiary care hospital. The prevalence of CVRF was compared to that of 600 outpatients without inflammatory conditions. To analyze CVD-associated factors, odds ratio (OR) values were calculated by conditional logistic regression analysis. Significant variables in the univariate analysis were then introduced in a multivariate analysis with a backward stepwise approach. Patients with psoriatic arthritis had higher frequencies of hypertension (36% vs 23%, OR 2.4, 95%CI: 1.6-2.7, P<0.0001), diabetes (13.8% vs 5%, OR 2.8, 95%CI: 1.7-4.3, P<0.0001), obesity (35% vs 22%, OR 2.1, 95%CI: 1.5-2.8, P<0.0001) and tobacco use (26% vs 21%, OR 1.4, 95%CI: 1.0-1.8, P<0.05). More PsA patients had CVD compared to non-inflammatory patients (9.4% vs 5.8%, OR 1.68, 95%CI: 1.02-2.76, P<0.05). Independent CVD-associated factors were: an age of onset of psoriasis >40years (OR 3.4, 95%CI: 1.1-10.0, P<0.05), a high number of swollen joints during evolution (OR 2.9, 95%CI: 1.1-8.0, P<0.05), hypertension (OR 5.3, 95%CI: 1.6-17.6, P<0.01) and dyslipidemia (OR 2.6, 95%CI: 1.0-7.2, P<0.05). Cardiovascular risk should be carefully evaluated in patients with PsA whose disease presents a high inflammatory burden and in those with late-onset psoriasis.

Heart Failure in Constrictive Pericarditis Improves Rapidly with Medical Therapy in Patients with Higher Inflammatory Burden

Introduction Diastolic heart failure is the primary pathophysiologic manifestation of constrictive pericarditis. Pericardiectomy is the choice of treatment for patients who fail medical therapy. Constrictive pericarditis may be chronic or transient inflammatory or a combination of both. Medical therapy with anti-inflammatory drugs improves the pericardial inflammation in patients with increased delayed hyper-enhancement (DHE) on cardiac magnetic resonance (CMR) imaging. The evolution of constrictive physiology, heart failure manifestations and outcomes with such treatment need more study. Hypothesis We hypothesize that in inflammatory constrictive pericarditis, anti-inflammatory therapy may reduce the need for pericardiectomy by reducing inflammation and improving heart failure symptoms. We also hypothesize that patients with severe inflammation have the best response to medical therapy. Methods Consecutive patients diagnosed with constrictive pericarditis and pericardial inflammation as evidenced by their CMR and elevated inflammatory markers were included. Patients were treated as per standard of care with anti-inflammatory therapy and diuretics, and followed on an outpatient basis. CMR imaging was obtained at approximately 6 month intervals. Patients received pericardiectomy if they had persistent constrictive physiology and signs and symptoms of heart failure despite optimal therapy. Baseline characteristics, laboratory values, echocardiographic and CMR data were collected. Pericardial delayed hyper-enhancement was quantified by measuring the volume of DHE using an intensity cutoff of >6 SD above normal septal myocardium. Results A total of 44 patients with 123 CMRs were included. Pericardiectomy was performed in 19 patients. Mean age was 57.9 ± 14.5 years and 9 (28%) patients were female. Mean left ventricular ejection fraction was 59 ± 6.5 %. There were no significant baseline differences between patients who underwent pericardiectomy and those who did not. On mixed model logistic regression analysis, the odds of having constrictive physiology was reduced by 49% (95% CI: 14%–70%, P=0.011) per year of optimal medical therapy. Patients with DHE above median had a 69% lower risk of needing pericardiectomy (HR: 0.31, 95%CI: 0.10–0.95, P=0.039) (Figure. 1). Conclusions With optimal anti-inflammatory therapy, constrictive physiology resolves significantly over time. The risk of requiring pericardiectomy is lower in patients with higher pericardial delayed hyper-enhancement at baseline.

MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation

Matrix metalloproteinase (MMP)-12, S100A8/A9, and S100A12 are involved in innate immune responses. We addressed whether different aspects of oral health and non-disease-related covariates influence their levels in saliva. 436 participants were clinically examined, completed a health questionnaire, and provided stimulated saliva. Salivary levels of MMP-12, S100A8/A9, and S100A12 were determined by enzyme-linked immunosorbent assays. Lower MMP-12 levels were observed in individuals 40–64 years old (yo) compared to < 40 yo, and higher S100A8/A9 levels were found in individuals > 64 yo compared to 40–64 yo. Smokers exhibited lower MMP-12 and S100A12 levels compared to non-smokers. All three proteins were elevated in individuals with bleeding on probing (BOP) > 20% compared to those with BOP ≤ 20%, and the S100A8/A9 levels were higher in individuals having ≥ 10% gingival pocket depths (PPD) ≥ 4 mm compared to the ones with shallow pockets < 4 mm. The extent of alveolar bone loss or presence of manifest caries did not alter any of the markers. MMP-12, S100A8/A9, and S100A12 levels were higher in participants with high periodontal inflammatory burden. All three proteins correlated positively to BOP, PPD, and to several inflammatory mediators. The explanatory variables for MMP-12 in saliva were age, smoking, presence of any tumor, and percentage of PPD ≥ 4 mm. The determinant of salivary S100A8/A9 was percentage of BOP, while S100A12 levels were associated with percentage of BOP and presence of any tumor. Taken together, MMP-12 and the S100/calgranulin levels in saliva reflect different aspects of periodontal inflammation. Smoking and age should be taken into account in further investigation of these proteins as biomarker candidates of periodontal disease.

Atypical Presentation of Incomplete Kawasaki Disease: A Peripheral Facial Nerve Palsy

BackgroundKawasaki disease (KD) is a multisystem vasculitic disease. Coronary artery aneurysms (CAAs) are the most important and life-threatening complication of KD. Various neurologic complications have been described to occur in 1–30% of patients with KD, but peripheral facial nerve palsy (FNP) is rare (0.9%). Case ReportWe describe a 5-month-old male infant who presented to us with unilateral left infranuclear FNP in the convalescent phase (day 18 of illness) of incomplete KD. The initial diagnosis was not made during the first 10 days of illness (therapeutic window for immunoglobulin treatment) as he was suspected to have hand-mouth-foot disease. We believe that both the delay in diagnosis and treatment of an atypical presentation of KD, combined with the more severe vasculitis and inflammatory burden reported in these cases, contributed to the development of CAA in our patient. Why Should An Emergency Physician Be Aware of This?This case highlights the importance of considering KD diagnosis in children with prolonged unexplained fever, even with incomplete diagnostic features, as well as the need to be aware of unusual manifestations, such as FNP. Atypical cases like this may be at increased risk of CAA because of delayed diagnosis and a higher inflammatory burden; therefore, a more aggressive treatment approach may be necessary.

Accelerated Infliximab Dosing Increases 30-Day Colectomy in Hospitalized Ulcerative Colitis Patients: A Propensity Score Analysis.

Standard outpatient induction dosing of infliximab (IFX) may not be effective in hospitalized ulcerative colitis (UC) patients with higher inflammatory burden and colectomy risk. Our aim was to determine whether initial IFX induction dose affects 30-day colectomy rate and other disease-related outcomes. IFX-naive hospitalized UC patients receiving at least 1 inpatient 5 mg/kg (SD) or 10 mg/kg (HD) IFX induction dose were included. Baseline demographics and admission-related characteristics were documented. Propensity score based matching was used to control for provider bias introduced due to nonprotocolized choice of IFX dose. The primary outcome was 30-day colectomy; secondary outcomes included the need for an accelerated induction IFX (AD), length of stay (LOS), 90-day and 1-year colectomy, and complications. Of 146 (120 SD/26 HD) patients included, 25 (17.1%) underwent colectomy by 30 days, 33 (22.6%) by 90 days, and 41 (28.1%) by 1 year. In 21 propensity score matched dyads (n = 42) treated with SD or HD, colectomy rates and LOS were similar. SD patients more often needed AD (23.8% vs. 0%, P = 0.048) and AD patients progressed to colectomy more rapidly within 30 days compared to non-AD (P = 0.001). Female sex and hypoalbuminemia were associated with significantly increased odds of needing AD on both univariate and multivariate analyses. In our propensity score based analysis, receiving accelerated IFX dosing after an initial SD infusion was associated with significantly higher 30-day colectomy rates in hospitalized acute UC patients. The most effective dosing strategy in this population remains unclear and prospective randomized studies are needed.

Certolizumab pegol in a heterogeneous population of patients with moderate-to-severe rheumatoid arthritis.

Aim:To determine the efficacy and safety of certolizumab pegol for the treatment of rheumatoid arthritis in a real-world setting.Materials & methods:Patients with moderate-to-severe rheumatoid arthritis who initiated therapy with certolizumab were followed for 12 weeks. Response was assessed with Disease Activity Score of 28 joints, European Ligue Against Rheumatism criteria and Simplified Disease Activity Index. Predictors of response were analyzed with binary logistic regression models.Results:Statistically significant decreases in tender and swollen joint counts, laboratory parameters and use of corticosteroids and disease-modifying antirheumatic drugs were found. Disease activity also significantly diminished. Higher Disease Activity Score of 28 joints at baseline was the main predictor of response. No severe adverse events were reported.Conclusion:Certolizumab was effective and well tolerated, particularly in the subpopulation with higher inflammatory burden at baseline.

An exploratory factor analysis of inflammatory and coagulation markers associated with femoral artery atherosclerosis in the San Diego Population Study

Background and aimsSeveral biomarkers of inflammation and coagulation have been implicated in lower extremity atherosclerosis. We utilized an exploratory factor analysis (EFA) to identify distinct factors derived from circulating inflammatory and coagulation biomarkers then examined the associations of these factors with measures of lower extremity subclinical atherosclerosis, including the ankle-brachial index (ABI), common and superficial femoral intima-media thickness (IMT), and atherosclerotic plaque presence, burden, and characteristics. MethodsThe San Diego Population Study (SDPS) is a prospective, community-living, multi-ethnic cohort of 1103 men and women averaged age 70. Regression analysis was used to assess cross-sectional associations between the identified groupings of biomarkers (factors) and the ABI and femoral artery atherosclerosis measurements. ResultsTwo biomarker factors emerged from the factor analysis. Factor 1 consisting of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen was significantly associated with higher odds (OR = 1.99, p < 0.01) of a borderline ABI value (0.91–0.99), while Factor 2 containing D-dimer and pentraxin (PTX)-3 was significantly associated with higher common femoral artery (CFA) IMT (β = 0.23, p < 0.01) and lower ABI (β = −0.03, p < 0.01). ConclusionsTwo groupings of biomarkers were identified via EFA of seven circulating biomarkers of inflammation and coagulation. These distinct groups are differentially associated with markers of lower extremity subclinical atherosclerosis. Our findings suggest that high inflammatory and coagulation burden were better markers of more severe lower-extremity disease as indicated by low ABI rather than early atherosclerotic lesion development in the femoral artery.

Disease severity impacts the relationship of apelin with arterial function in patients with rheumatoid arthritis.

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p ≥ 0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p ≤ 0.05). In stratified analysis, apelin was associated with CSP (partial r = - 0.33, p = 0.01), CPP (partial r = - 0.26, p = 0.04), PPamp (partial r = 0.27, p = 0.03), and Pf (partial r = - 0.33, p = 0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r = - 0.24, p = 0.05) in those with a DAS28 joint < 2.8 (median value) (partial r = - 0.24, p = 0.05) but not ≥ 2.8, and to CSP (partial r = - 0.36, p = 0.003) in those with an erythrocyte sedimentation rate < 13mm/h (median value) but not ≥ 13mm/h. Apelin is associated with reduced pressure pulsatility in RA patients without but not with a high inflammatory burden. A loss of apelin protective effects on arterial function may contribute to the link between RA severity and cardiovascular risk.

P186 Outcomes of maintenance ustekinumab therapy for Crohn’s disease based on inflammatory burden: A post-hoc analysis of the UNITI trials

Patient inflammatory burden has been postulated to predict response to anti-inflammatory therapies. Ustekinumab(UST) is the only approved anti-IL-12/23 mAb for the treatment of Crohn’s disease (CD) and the PBO-controlled UNITI registration trials present an opportunity to test this hypothesis. We evaluated clinical outcomes to 90 mg q8 and q12wk SC treatment strategies based on inflammatory biomarkers C-reactive protein (CRP) and fecal calprotectin (fCal). In UNITI 1 (anti-TNF therapy failures) and UNITI 2 (conventional therapy failures), patients were randomised to PBO, UST 130 mg IV, or UST ~6mg/kg IV. At 8weeks, all responders to IV induction therapy participated in IM-UNITI and were randomised to SC maintenance treatment with PBO, UST 90 mg q8wks, or UST 90 mg q12wks. Clinical endpoints were assessed after 44 weeks of maintenance therapy. Results were stratified by inflammatory burden based on CRP and fCal. For CRP, inflammatory burden categories used were ≤5, >5 and ≤10, and >10 mg/l. For fCal, inflammatory burden categories used were <250 and ≥250 mg/kg. When patients were stratified by inflammatory burden at baseline (BL) of induction (i.e. before IV dose), CRP thresholds discriminated patients in the 90 mg q12wk group into those more or less likely to achieve clinical endpoints at wk44 of maintenance. This finding is also supported by fCal stratification at BL of induction (i.e. before IV dose).Stratification at BL of maintenance provides greater distinction between UST doses. Maintenance week44 results stratified by CRP are shown in Figure 1. They suggest that a CRP >10 mg/l at maintenance BL (i.e. before first SC dose) discriminates a high inflammatory burden population that benefited from UST 90 mg SC q8wk dosing vs. q12wk dosing. Response and remission rates were similar between UST SC q8wk and q12wk dosing in patients with maintenance BL CRP ≤5mg/l and between 5and10 mg/l. Similar effects were seen at maintenance wk44 endpoints using fCal (Figure 2). Those with a higher inflammatory burden(fCal >250 mg/kg) at maintenance BL more clearly separated from PBO in q8wk group(56.4% vs. 33.8% remission, p = 0.002) vs. q12wk group (46.1% vs. 33.8% remission, p = 0.065). CD patients with low inflammatory burden based on biomarkers CRP and fCal at BL and/or at initiation of maintenance therapy can benefit from q8 or q12wk maintenance dosing with UST, while those with high inflammatory burden are likely to need q8wk to maintain benefit. Clinical endpoints at week 44 of IM-UNITI, stratified by baseline CRP Clinical endpoints at week 44 of IM-UNITI, stratified by baseline fecal calprotectin

P192 SURGICAL OUTCOMES IN CHILDREN HOSPITALIZED WITH UC RECEIVING INTENSIFIED INFLIXIMAB INDUCTION

Hospitalized children with severe Ulcerative Colitis who are steroid unresponsive often receive Infliximab (IFX). Standard IFX induction dose is 5mg/kg weeks 0, 2 & 6. The rationale for intensified infliximab induction (III) in severe UC is: higher inflammatory burden, increase in IFX clearance & stool losses. There are no pediatric data on the outcomes of III. Report clinical outcomes of hospitalized children with severe colitis who received III. Retrospective review of patients <18 years hospitalized October 2011-June 2017 with severe UC who received their 1st induction IFX. Patients were divided into 2 groups: III (IFX ≥15mg/kg in ≤14 days) vs controls (<15mg/kg in <14 days or >15mg/kg in >14 days). Data included patients’ demographics, PUCAI, CRP, albumin, prior therapy & clinical outcomes. We used two-sample t-test and Wilcoxon rank-sum for parametric and non-parametric data respectively to assess association between clinical variables & colectomy outcome. We identified 40 patients. Mean age at IFX induction 13.5 (± 3.7) years. All patients had prior steroid exposure. 2/40 patients had prior biologic exposure (Adalimumab). 16/40 patients received III. Data suggested higher CRP in the III group, but not reaching statistical significance. The two groups were similar in age, albumin and PUCAI scores at the time of first infliximab. 43% children in III group underwent colectomy vs 37% controls. Surgery occurred during the same hospitalization as IFX initiation for 57% of patients with III vs none in controls. Median time from 1st IFX to colectomy in III group was 30 days (range 13-107) vs 150 days (26-910), (P=0.0502). Our study suggests comparable clinical features between patients who received intensified IFX induction and controls. Although the data suggested shorter time to colectomy with intensified IFX induction without statistical significance, colectomy rate was relatively similar to non-intensified infusions.

Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study

Conventional coronary artery disease risk factors might potentially explain at least 90% of the attributable risk of coronary artery disease. To better understand the association between the pre-industrial lifestyle and low prevalence of coronary artery disease risk factors, we examined the Tsimane, a Bolivian population living a subsistence lifestyle of hunting, gathering, fishing, and farming with few cardiovascular risk factors, but high infectious inflammatory burden. We did a cross-sectional cohort study including all individuals who self-identified as Tsimane and who were aged 40 years or older. Coronary atherosclerosis was assessed by coronary artery calcium (CAC) scoring done with non-contrast CT in Tsimane adults. We assessed the difference between the Tsimane and 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores higher than 100 were considered representative of significant atherosclerotic disease. Tsimane blood lipid and inflammatory biomarkers were obtained at the time of scanning, and in some patients, longitudinally. Between July 2, 2014, and Sept 10, 2015, 705 individuals, who had data available for analysis, were included in this study. 596 (85%) of 705 Tsimane had no CAC, 89 (13%) had CAC scores of 1-100, and 20 (3%) had CAC scores higher than 100. For individuals older than age 75 years, 31 (65%) Tsimane presented with a CAC score of 0, and only four (8%) had CAC scores of 100 or more, a five-fold lower prevalence than industrialised populations (p≤0·0001 for all age categories of MESA). Mean LDL and HDL cholesterol concentrations were 2·35 mmol/L (91 mg/dL) and 1·0 mmol/L (39·5 mg/dL), respectively; obesity, hypertension, high blood sugar, and regular cigarette smoking were rare. High-sensitivity C-reactive protein was elevated beyond the clinical cutoff of 3·0 mg/dL in 360 (51%) Tsimane participants. Despite a high infectious inflammatory burden, the Tsimane, a forager-horticulturalist population of the Bolivian Amazon with few coronary artery disease risk factors, have the lowest reported levels of coronary artery disease of any population recorded to date. These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body-mass index, no smoking, and plenty of physical activity. The relative contributions of each are still to be determined. National Institute on Aging, National Institutes of Health; St Luke's Hospital of Kansas City; and Paleocardiology Foundation.

Multicenter, Open-Label, Phase I/II Study of Tocilizumab, an Anti–Interleukin-6 Receptor Monoclonal Antibody, Combined with Gemcitabine in Patients with Advanced Pancreatic Cancer

Background: To assess the efficacy, safety and pharmacokinetics of tocilizumab + gemcitabine in patients with advanced pancreatic cancer. Methods: Patients with treatment-naive advanced pancreatic cancer and high inflammatory burden (C-reactive protein ≥ 2 mg/dl) without obvious infections received tocilizumab (8 mg/kg) intravenously every 2 weeks with intravenous gemcitabine (1,000 mg/m2) on days 1, 8 and 15 of each 4-week cycle until disease progression or study withdrawal. Interleukin-6 signalling inhibition biomarkers were measured. Efficacy analyses included overall survival, progression-free survival, tumour response and clinical symptoms. Adverse events and laboratory parameters were also assessed. Results: Fifteen patients received tocilizumab+gemcitabine. Tumour response was observed in two patients (13%). Six patients (40%) died within 2 months of treatment start. Median overall survival was 2.5 months (95% confidence interval, 1.4-5.8); median progression-free survival was 1.8 months (95% confidence interval, 0.8-3.6). Overall and progression-free survival tended to be longer in patients with modest than in patients with higher elevations of baseline C-reactive protein. Changes in C-reactive protein and IL-6 occurred. Although tocilizumab +gemcitabine was tolerable, results were inconclusive because of the brevity of the evaluation period resulting from the death or premature withdrawal of patients. Dose interruption attributed to haematologic toxicity was frequently observed. Conclusions: Tocilizumab+gemcitabine failed to show a clear clinical benefit in patients with advanced pancreatic cancer and high inflammatory burden. To evaluate conclusively the benefit of tocilizumab, future study designs should use a comparator treatment that does not interfere with interleukin-6 signalling and that includes better patient selection criteria.

Lipid Profile in Rheumatoid Arthritis and its Relation with Inflammatory Markers

Introduction: Rheumatod Arthritis (RA) is the most common autoimmune arthritis, associated with accelerated atherogenesis and increased cardiovascular mortality. An apparent lipid paradox exists in RA. Active RA with high burden of inflammatory markers leads to low levels of LDL-C, Total cholesterol, HDL-C and vice versa in inactive disease. The current study was aimed to assess the relationship between inflammatory markers and lipid components in RA patients. Methods: The study was conducted at a Rheumatology clinic of a Tertiary care hospital and included 203 RA patients. Fasting blood samples were drawn for lipid analysis and inflammatory markers (ESR/CRP). Relationship between the two was assessed using Pearson’s correlation method. Results: Out of 203 patients, 180 were female (89%) and 23 were males (11%). Mean duration of disease was 2.55 ± 2.09 years and mean age was 47 ± 10.9 years. The mean total cholesterol, HDL-C, LDL-C and triglycerides were 198.6 ± 43.6 mg/ dl, 41 ± 8.2 mg/dl, 109 ± 28 mg/dl and 224.8 ± 89 mg/dl respectively. Mean ESR was 37mm in 1st hour and mean CRP was 9.6 mg/dl. A statistically significant negative correlation was found between CRP and total cholesterol (p<0.001), CRP and HDL-cholesterol (P<0.001), CRP and LDL-cholesterol (P<0.001). Similarly, a negative correlation was found between ESR and HDL-cholesterol (p<0.001). However, no significant correlation was found between ESR and total cholesterol and/or LDL-cholesterol. Triglycerides and VLDL-cholesterol were found to have no significant correlation with inflammatory markers in our study. Conclusion: RA is a disease with lipid paradox. A high inflammatory burden is associated with low level of HDL-C, LDL-C and Total cholesterol.