Search

In the last years, due to new regulatory guidelines requiring a stringent documentation of cardiovascular (CV) safety of novel drugs for type 2 diabetes, cardiovascular outcomes safety trials (CVOTs) are requested. CVOTs increase the knowledge about the safety profile of the new drugs, but they have intrinsic limits that make difficult their transferability to clinical practice. For this reason, real world evidence is considered an important complement to experimental data. Among the glucagon-like peptide-1 receptor agonists, liraglutide in the LEADER CVOT demonstrated superiority in reducing the risk of major CV events (MACEs) vs. placebo. We conducted an observational, retrospective, longitudinal study based on 307 patients with T2DM treated with liraglutide under routine clinical practice conditions. Real world impact of liraglutide on metabolic control, CV risk factors, hypoglycemia and CV events was assessed. Improvements during 36 months were found in HbA1c (–1.0%; p Incidence of MACEs in this cohort was lower than in the LEADER study (2.59 vs. 3.4 events per 100 person-years), confirming CV safety of liraglutide even in the real world. On the other hand, a higher incidence of CV event in patients with established CV disease was documented (8.1 events per 100 person-years), in spite of the use of liraglutide. In conclusion, 36-month durability and CV safety of liraglutide were documented in a real world cohort of T2DM patients, with sustained benefits on a large array of CV risk factors.

To investigate the association of alleles of the 3′ immunoglobulin heavy-chain regulatory region 1 (3′RR-1) enhancer hs1.2 in patients with type 1 diabetes (T1D). Eighty-one patients with T1D [among which 12 had concomitant coeliac disease (CD) and 25 an autoimmune thyroid disease (AITD)] were compared to 248 healthy individuals. All subjects were recruited from the same geographical area. Blood samples were collected from all patients and a nested PCR was performed to amplify the core of the 3′RR-1 and detect the alleles of the hs1.2 enhancer. Allele distribution in healthy individuals was significantly different when compared to that of patients with T1D (p

Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from difficult MPN associated symptoms which impact quality of life (QoL). The impact of initial cytoreduction on ET/PV symptoms, resulting toxicity and QoL have not been prospectively studied. Methods: MPD-RC 112 trial (NCT01258856) randomized 168 therapy-naive (hydroxyurea [HU] Results: Patients: Of 168 randomized pts (86 HU, 82 PEG), 164 (98%) completed the survey package at baseline and 151 (HU 83%; PEG 98%) completed at least 1 survey during treatment. Median age was 61 (range 18-87) with 70 (42%) females; 81 (48%) / 87 (52%) with ET / PV; 46 (27%) had a history of a thrombosis. 119 (71%) received prior HU (up to 3 months). Baseline characteristics were balanced between arms with the exception of age (median HU 63 vs. PEG 60 yrs; p=0.02). Baseline Symptom Burden /QoL: Mean MPN-SAF Total Symptom Score (TSS), scale 0 [absent]-100 [worst imaginable] was 15.8 (SD 12.6; range 0-62.0) with means of 15.1 (SD 12.6) / 16.5 (SD 12.6) for ET / PV which were slightly lower than reported means of a previous cohort receiving any line of treatment (Scherber RM, JCO 2012). Median number of moderate (defined as score >=3) symptoms in ET patients was 3.0 and PV 4.0. Most common moderate symptoms were fatigue (65.9%), insomnia (37.2%), numbness (33.5%) , itching (29.9%), dizziness (27.4%), early satiety (26.8%) , headache (23.2%), sad mood (23.2%), inactivity (22%), concentration (20.7%). 50.6% of patients had one or more symptom with a score >=6. Mean QLQ-C30 global health status/QoL (GHS/QoL) was 70.8 (SD 21.9) - comparable to a general population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). At baseline, TSS, symptoms, and QoL were similar between treatment arms. In patients with TSS >20 at baseline (highly symptomatic, n=50; ET:20, PV:30), median TSS was 28.0 (range 20.0 to 62.0); the highest scored symptom was fatigue (median=7.0), itching (median=4.5) and insomnia (median=4.0). Impact of Therapy on Symptom Burden/QoL: On HU, pts experienced worsening QoL (physical, cognitive functioning, HRQoL) and some persistent or transient worsened symptoms (inactivity, concentration (p 20, n=50), improvements in weight loss, abdominal discomfort, fatigue, itching, fever, early satiety (12 m.) were observed in pts on HU. For PEG, in highly symptomatic pts, improvements were observed for overall TSS score, fatigue, inactivity, night sweats, and itching (with similar toxicities to all PEG patients). ELN Response and Symptom Burden/QoL: Among the 133 pts with 12-mo symptom data, complete hematologic response (CHR) rate was 43%. Inactivity and sad mood were worse in those patient achieving a CHR (inactivity: CHR worsening 0.68 vs PHR/NR better 0.26; p=0.03; sad mood: CHR worsening 0.67 vs PHR/NR better 0.67, p=0.002)). These latter changes were not related to higher doses utilized (in either arm), suggesting obtaining CHR may have negative effects on patient symptoms. Conclusions:In pts with a significant baseline MPN symptom burden, cytoreductive therapy has both a beneficial impact on baseline MPN symptom burden but also leads to therapy associated toxicity, although different patterns of efficacy and toxicity between HU and PEG. Achievement of a CHR in PV/ET may be associated with higher rates of drug related toxicities, and the value of achieving CHR may need further validation. Disclosures Mesa: Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Genentech: Research Funding; Pfizer: Research Funding. Mascarenhas:Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Promedior: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Rambaldi:Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy. Yacoub:Novartis: Honoraria, Speakers Bureau; Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Harrison:Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Mead:Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Kessler:Sangamo: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Biomarin: Research Funding. Kremyanskaya:Incyte: Research Funding. Rampal:Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding; Celgene: Honoraria. Hoffman:Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Formation Biologics: Research Funding; Summer Road: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment.

Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) includePolycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). These stem cell disorders carry a propensity to evolve into acute myeloid leukemia (MPN-blast phase [BP] or post-MPN AML) with a dismal prognosis not meaningfully improved by conventional anti-leukemia therapy. Thus, MPN-BP is an urgent unmet clinical need. Responses in patients with MPN-BP to hypomethylating agents and single agent ruxolitinib have been reported. More recently, combination of ruxolitnib and decitabine has demonstrated synergistic activity in vitro in cells derived from patients with MPN-BP and from a murine model of MPN-BP (Rampal et al PNAS 2014). These observations led us to explore the safety of combined decitabine and dose escalation of ruxolitinib in MPN-BP. Objective: To establish the maximum tolerated dose (MTD) of ruxolitinib in combination with a fixed dose of decitabine (DEC-RUX). Methods: We conducted an open label Phase I trial in patients with MPN acceleration phase (AP) as defined by 10%-19% blasts in the peripheral blood or bone marrow or a diagnosis of MPN-BP as defined by ≥ 20% blasts in the blood or bone marrow, following a previous diagnosis of ET, PV or PMF. Patients were enrolled in a standard 3+3 phase I design with an MTD defined as a dose Results: A total of 21 patients were accrued to study (Table 1). The median age was 63 years (range 48-88). 52% carried a diagnosis of MPN-AP, and 48% carried a diagnosis of MPN-BP. 29% of patients and 24% of patients had prior exposure to ruxolitinb and decitabine, respectively. The median number of cycles received varied from 10.5 cycles in the 10mg BID cohort to 2 and 2.5 cycles in the 25mg BID and 50mg BID cohorts, respectively (Table 2). The most common Grade 3/4 non-hematologic AEs observed were due to infection in all dosing cohorts. In terms of hematologic toxicity, treatment emergent Grade 3/4 anemia was observed in 1 patient in each of the 10mg BID, 15mg BID, and 50mg BID cohorts. Grade 3/4 leukopenia was observed in only 1 patient at the 50mg BID cohort, and Grade 3/4 thrombocytopenia was observed in 2 patients in the 10mg BID cohort and 1 patient in the 15mg BID cohort. DLT rate was below 33% for all dose levels so the MTD was not reached. The most common reason for ending study treatment was toxicity/adverse events (33%) followed by disease progression (22%). 9 patients died during study or follow-up. Of those, 5 (56%, 2 in 10mg BID cohort, 1 in 15mg BID cohort, 2 in 50mg BID cohort) died of infection, 3 (33%, 1 in each of 10mg, 25mg, and 50mg BID cohorts) of progressive disease, and 1 (11%, 25mg BID cohort) of hemorrhage. The median overall survival for patients on study was 10.4 months (95% CI 3.3 mo - not reached). CR/CRi as best response was observed in 7/21 patients (33%, 95% CI 15-57%; 2 CR, 5 CRi; Table 2). Conclusions: DEC-RUX combination therapy was safely administered to patients with MPN-AP/BP and an MTD was not reached. Based on pre-clinical data, observed safety profile, duration of treatment, and clinical responses in this phase I trial, the Recommended Phase II Dose of RUX was selected as 25mg BID for an induction cycle followed by 10mg BID in all ensuing cycles. Molecular and bone marrow pathology responses will be presented at the meeting. Disclosures Mascarenhas: Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Janssen: Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Hexner:Blueprint medicines: Consultancy; Novartis: Research Funding. Abboud:Alexion: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Teva: Research Funding, Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria; Baxalta: Honoraria; Seattle Genetics: Research Funding; Gerson and Lehman Group: Consultancy; Cardinal: Honoraria. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Celgene: Research Funding; Galena: Consultancy; Ariad: Consultancy; Gilead: Research Funding; CTI: Research Funding.

We conducted a two-stage Simon phase II, multi-center study in two groups: related and unrelated donor transplants. Based on the results of a previously conducted prospective study (MPD-RC 101, Rondelli et al, Blood, 2014) demonstrating relatively poor outcome in the unrelated donor arm due to high non-relapse mortality and graft failure (GF), we sought to improve this noted disparate outcome. The hypothesis driving this trial was that pre-transplant JAK1/2 inhibition would result in an increase in performance status, reduction in splenomegaly and inflammatory cytokine expression leading to improved HCT outcome. In the unrelated arm in the first 11 patients, the trial was to be terminated if 6 or more failures (GF or death due to any cause by 100 days post-transplant) were observed. In the related arm in the first 11 patients, the trial was to be terminated if 3 or more failures were observed. Key eligibility criteria included diagnosis of primary MF or post-PV MF or post-ET MF, age 18-70 years, and DIPSS int-2/high risk disease or int-1 risk disease with at least one additional risk factor. Patients could have received up to 6 months of ruxolitinib prior to enrollment provided that there was no evidence of loss of response to ruxolitinib during this period. Ruxolitinib was given for 56 days followed by a 4-day taper ending day -6. The conditioning regimen utilized was IV fludarabine 40 mg/m2 IV and IV busulfan 2.0 mg/KBW IV once daily for 4 days from days -5 to -2. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Patients undergoing unrelated donor HCT also received low dose thymoglobulin (0.5 mg/KBW on day -3/2.0 mg/KBW on day -2 & day -1). The study has enrolled 21 patients (related, 7; unrelated, 14) with a median age of 59 years (range 39-70). 17 (81%) patients had palpable splenomegaly with median spleen size of 11 cm, and 16 patients had int-2/high risk disease. Of the 21 patients, 19 patients received transplantation (related 5/7 [71%], unrelated 14/14 [100%] underwent transplant). Two patients in the related arm did not proceed with transplantation as one progressed to acute myeloid leukemia (baseline blast count 14%) and another experienced sudden death of unknown cause the day after starting ruxolitinib. In addition, there was one GF in the related arm. Due to these 3 failures in the related arm, further enrollment was stopped in this arm per protocol criteria. In the unrelated arm, there were 4 failures (Table 1), and the study met the protocol criteria for further enrollment. Mean percent reduction from baseline to day -9 in palpable spleen length below the left costal margin was 30% (p=0.04) in 12 patients with palpable spleen. 5/12 (42%) had any reduction, and 4/12 (33%) had ≥50% reduction. From baseline to best score on day -9 or day -5, 11/19 (58%) patients with data had any improvement in MPN-SAF Total Symptom Score, and 7/19 (37%) had ≥50% reduction. Of the 19 patients undergoing transplant, ruxolitinib was tapered off successfully in all patients with no significant withdrawal syndrome or delay in transplant noted. In the pre-transplant phase, most common Grade 3 or higher toxicity considered to be related to ruxolitinib was anemia (6/21, 29%), and one patient had legionella pneumonia deemed not related to ruxolitinib. Median time to neutrophil recovery (> 0.5 x 109/L) and platelet recovery (>20 x 109/L) was 19 and 19.5 days. By day 100, 7/19 (37%) experienced Grade 2-4 acute GVHD (G2 in 5, G3 in 2). In the first 30 days post HCT, most common Grade 3 or higher toxicity was febrile neutropenia seen in 5/19 (26%) patients. In all 21 patients from time of registration with median follow-up of 5.8 months, 6-mo overall survival was 75% (95% CI 44-90%). For the 19 transplant recipients, 6-mo OS was 83% (95% CI 55-94%) from date of transplant. Conclusions: Stage 1 trial results highlight important observations. First, ruxolitinib may not be suitable for all myelofibrosis patients pre-transplant, eg, alternative approaches might be more appropriate in the context of accelerating disease. Second, we demonstrated a safe approach for tapering ruxolitinib prior to transplant which allowed patients to commence conditioning with reduced spleen size and symptoms. Third, pre-transplant ruxolitinib does not appear to have any adverse impact on early post-HCT outcomes following unrelated donor transplant, although Stage 2 enrollment will be required to better assess the potential benefits of this approach. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Mascarenhas:Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding.

Background: Cytoreductive therapy with hydroxyurea (HU) has been considered first line therapy for patients with high risk polycythemia vera (PV) and essential thrombocythemia (ET) since the results of the PVSG-08 trial demonstrated thrombotic risk reduction (Fruchtman SM et al 1997) for PV and PT1 for ET (Harrison CN et al 2005). Although HU is well tolerated by most patients and has been shown to reduce thrombotic risk in this setting, concern regarding the leukemogenic potential of this oral ribonucleotide reductase inhibitor balanced by the observation of molecular responses with interferon-α (IFN-α) led us to compare the clinical response and tolerability of pegIFN-α (PEG) and HU in a global, randomized, phase III trial. Methods : MPD-RC 112 trial (NCT01258856) enrolled patients with high risk (age >60 years, history of thrombosis, extreme thrombocytosis, symptomatic splenomegaly, uncontrolled cardiovascular risk factors), newly diagnosed ( Results: Patients: The MPD-RC 112 trial involved 24 centers in 6 countries; enrollment began 09/2011 and concluded 7/2016 prior to full accrual due to study drug availability with 168 patients enrolled (Table 1 for 75 patients in the interim analysis). There was no imbalance between arms with respect to history of thrombosis, erythromelalgia, diabetes, hypertension, but age was significantly older on HU. This remained true when analyzing by ET/PV disease strata with the exception of diabetes which was slightly imbalanced within the PV cohort (HU 5/23, 22%; PEG 0/21, 0%; p Response: CHR and PHR were observed in 13 (33%) and 14 (36%) patients for an overall response rate (ORR) of 69% (27/39) for HU, and 10 (28%) and 19 (53%) for an ORR of 81% (29/36) for PEG (CHR comparison p=0.60 based on z-test which did not cross either testing boundary). 10 patients randomized to HU were not evaluable for 12-month response due to never initiating treatment (n=3) or early study discontinuation for AEs (n=1), patient withdrawal (n=5), or treatment non-compliance (n=1). 3 patients were not evaluable for response on PEG due to early study discontinuation for AEs (n=1), physician decision (n=1), or patient withdrawal (n=1). Excluding patients who never initiated treatment did not impact the primary endpoint comparison (HU 13/36, 36%; PEG 10/36, 28%; p=0.45). For ET, CHR and PHR were observed in 7 (44%) and 4 (25%) patient on HU, and 6 (40%) and 6 (40%) for PEG (CHR comparison p=0.83). For PV, CHR and PHR were observed in 6 (26%) and 10 (44%) patients on HU, and 4 (19%) and 13 (62%) for PEG (CHR comparison p=0.58). Normalization of spleen by palpation at 12 months was seen in 2/7 (29%) and 5/7 (71%) of the HU and PEG treated patients with palpable spleen at baseline, respectively. Among 38 PV patients, rate of phlebotomy use at 12 months was 0/18 (0%) vs 5/20 (20%) on HU and PEG (p=0.02). From baseline to best score through 12 months, 9/28 (32%) and 12/34 (35%) patients with data on HU and PEG, respectively, had a ≥50% reduction in MPN-SAF Total Symptom Score (p=0.79). Toxicity: No Grade 4 AEs occurred in either treatment arm. Overall, Grade 3 AEs occurred in 5/36 (14%) HU patients and 16/36 (44%) PEG patients (Grade 3 hematologic: 4/36 [11%] HU vs 8/36 [22%] PEG; Grade 3 non-hematologic: 5/36 [14%] HU vs 16/36 [44%] PEG). See Table 2 for Grade 3 AEs regardless of attribution occurring in >10% of patients in either arm. Conclusions: This interim analysis does not show a clear difference in primary endpoint of CHR between HU and PEG. A comparative analysis of the quality of life and symptom burden will provide further insight into the tolerability of these agents (Mesa et al ASH 2016). The final results of this pivotal trial will provide necessary data required to firmly establish the optimal first line therapy for patients with high risk ET/PV. Disclosures Mascarenhas: CTI Biopharma: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Roche: Research Funding; Novartis: Other: DSMB , Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Harrison:Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Vannucchi:Novartis: Honoraria, Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Kessler:Incyte: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

Balkan Endemic Nephropathy (BEN) is a kidney degenerative disease with a high incidence in the valleys of the Danube and tributary rivers. Many studies describe it as a multifactorial disease. Environmental as well immuno-inflammatory and genetic cofactors have been suggested to trigger the onset of the disease. Recently, high levels of C-reactive protein were demonstrated in BEN patients. We performed this study to evaluate the possible correlation of BEN with the polymorphism of the Ig heavy chain 3'Regulatory Region enhancer hsl.2 that is related to changes of consensus for trans activators binding within the DNA sequence and probably consequently autoimmune and inflammatory diseases. Therefore, we studied three cohorts: 1) 111 control subjects, 2) 95 BEN patients in dialysis therapy and 3) 133 components of a large family “J” in the same geographical area. The allelic frequencies of hsl.2 of BEN patients and family “J” components had similar decrease frequency of allele *1 and increase of allele *2 in respect to the controls. This trend suggests the association of allele *1 as a protective and allele *2 as a risk component for the disease. The presence of a consensus sequence for NF-Kb in the allele *2 may link the polymorphism to the inflammatory activity of BEN. This study supports the presence of an inflammatory pathway in BEN through the involvement of polymorphic enhancer hsl.2 influencing differently binding complexes and consequently the 3D structure of 3' Regulatory Region of IgH. Our work is the first study that clearly links BEN to a gene involved in the regulation of immune response.

Background Several studies underline the relevance of the genetic background for the response to therapy in the Rheumatoid Arthritis (RA). Objectives To study the polymorphism in the enhancer HS1,2A of the Ig heavy 3′ regulatory region (IgH 3′RR-1) as a biomarker of response to therapy in different phases of RA disease. Methods 535 RA patients were enrolled in the study, of which: A) 326 with an early RA (ERA), treated according to a tight control strategy (Methotrexate for three months, and if an incomplete response was seen after 3 months they started a combination with Tumor Necrosis Factor (TNF) blockers), B) 89 TNF-treated patients with a long-standing RA (TNF-treated LSRA) and C) 120 seropositive LSRA patients treated with Rituximab (RTX-treated LSRA), not responsive to previous DMARDs and/or TNF-blockers. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described (1). Diasease activity was assessed every three months according to the European League Against Rheumatism’s (EULAR) criteria. Results The polymorphism of the HS1,2A enhancer of the 3’ regulatory region respected the Hardy-Weinberg equilibrium in all the RA cohorts. The analysis of the genotype’s distribution of the HS1,2A enhancer showed a similar frequency of the 2/2 genotype in ERA patients (28.2%) compared to RTX-treated LSRA (21.7%, p=0.17 ), but lower than in TNF-treated LSRA (40.4%, p=0.03 vs ERA). Fifty percent of ERA patients reached a good-EULAR response at 3 months follow-up visit (FU) and 23% were in sustained EULAR-remission at 6 months FU. The percentage of good-EULAR response at 3-months FU and sustained EULAR-remission at 6-month FU was lower in ERA patients carrying the 2/2 genotype of HS1,2A enhancer compared with ERA patients without the 2/2 genotype (good-EULAR response: 35.9% vs 56.4%, OR(95%CIs): 0.43 (0.24-0.78); sustained EULAR-remission: 12.5% vs 26.1%, OR(95%CIs): 0.40 (0.18-0.91), respectively). Moreover, ERA patients carrying the 22 genotype were characterized by a more severe disease at baseline and by a higher percentage of subjects treated with TNF-blockers at 6 months FU compared to patients without the 22 genotype (26.1% vs 12.2%, p=0.01 ). In the cohort of TNF-treated LSRA patients (good-EULAR response: 32.6%) there was no association between the HS1,2A enhancer polymorphism and the response to therapy over time. The 25% of RTX-treated LSRA patients reached a good-EULAR response at 6 months FU. The percentage of good-EULAR response was more prevalent in RTX-treated LSRA patients carrying the 2/2 genotype compared to subjects without the 22 genotype (42.3% vs 20.2%, OR (IC 95%): 2.90 (1.15-7.32)). Conclusions The presence of the 2/2 genotype of HS1,2A enhancer seems to identify a more aggressive disease in ERA patients poorly responsive to DMARDs and it associates to a good EULAR response to RTX in seropositive LSRA. The demonstration of the presence of a binding site for NF-kB in the allele*2 of HS12A enhancer, (2) could explain the more aggressive phenotype. References Giambra V et al., Genes 2005 Frezza D et al., Ann Rheum Dis 2012. Disclosure of Interest None Declared

Objectives To evaluate the relationship between the response to therapy in early rheumatoid arthritis (ERA) and polymorphisms in the genes of molecules involved in inflammatory processes (TNF-α, TNF-RII, IL6, IL1b, IL1Ra, BAFF) or in the homeostasis of T and B cells (PTPN22, HS1,2 enhancer). Methods Two hundreds and eighty six ERA patients were enrolled in the study (females: 75.2%; mean age: 55.1±13.6 years; anti-CCP positive patients: 63.3%; IgA RF positive patients: 34.5%; IgM RF positive patients: 51.0%). All patients were treated with Methotrexate for three months, then with a combination with Tumor Necrosis Factor (TNF) blockers if they had an incomplete response after 3-month treatment period. DNA from patients was genotyped for the TNF-α (-308G>A and -238G>A), TNF-RII +196T>G, IL6 -174G>C, IL1b (-511C>T and +3953C>T), IL1Ra VNTR, BAFF -871C>T, PTPN22 +1858C>T, HS1,2A polymorphisms by polymerase chain reaction restriction fragment length polymorphism method. Clinical and laboratory data were recorded at baseline and every 3 months. The EULAR response criteria based on DAS were used to assess the disease activity after 3 and 6 months of follow-up (good response: DAS 1.2; sustained remission: DAS value of Results All the polymorphisms were in Hardy-Weinberg equilibrium. According to the multi-locus GMDR approach, TNF-308G>A, TNFRII+196T>G, IL1RA VNTR, IL1b-511, IL1b+3956, IL6-174G>C and BAFF-871C>T polymorphisms predicted the EULAR good response at 3 months correctly 60.9% of the time (Sign Test p=0.001 ). The EULAR sustained remission at 6 months was predicted 55.9% of the time by an ensemble of 5 polymorphisms (TNF-α-308, TNF-RII+196, IL1Ra VNTR, IL1β+3953, BAFF-871; Sign Test p=0.055 ). Conclusions The genetic background is a possible predictor of the response to therapy of patients with early rheumatoid arthritis. The analysis of gene-gene interactions, especially in genes of molecules related to the major inflammatory cytokines, will lead to a better understanding of the biological pathways underlying the therapeutic outcome in the earliest phases of the disease. Disclosure of Interest None Declared

Objective . Several studies underline the relevance of the genetic background for the response to therapy. We evaluated the relationship between the polymorphism of the HS1,2A enhancer, located in the 3’ regulatory region of the heavy immunoglobulin chain (IgH), and the response to B cell depletion therapy (BCDT) with Rituximab (RTX). Methods . Fifty rheumatoid arthritis (RA) patients (42 women; disease duration 13.9±10.6 years) treated with RTX, not responsive to previous DMARDs and/or TNFα inhibitors therapies, and 220 healthy subjects were enrolled in the study. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described. Disease activity was assessed every three months according to the European League Against Rheumatism’s (EULAR) criteria. Results . All RA patients were seropositive for at least one of the tested autoantibodies: rheumatoid factor (FR IgA, FR IgM e FR IgG), anti-cyclic citrullinated peptides (anti-CCP IgA, anti-CCP IgM e anti-CCP IgG) and anti-vimentin antibodies. RA patients had an increased frequency of the allele*2 (60.0%) of the HS1,2A enhancer compared to healthy subjects (42.0%; OR(95%ICs): 2.07 (1.33-3.22)). Patients with a good EULAR response at 6 months follow-up visit had an increased frequency of genotype 2/2 (47.1%) compared to poor-responders RA patients (genotype 2/2: 18.2%, OR(95%ICs): 4.00 (1.09-14.68)). All the patients with a good EULAR response had the allele*2, thus showing a possible association with the allele in this population. Conclusions . The presence of allele*2 seems to be related to a good response to BCDT with RTX in seropositive RA patients, thus highlighting the role of the HS1,2A enhancer in B cell maturation and class-switch recombination.