OBJECTIVES:We aimed to assess the outcome of a large Takayasu arteritis (TAK) cohort using the vasculitis damage index (VDI) and quality of life (QoL) scale, tools which have been validated for vasculitis.METHODS:Disease activity, damage and QoL were cross-sectionally evaluated in 165 TAK patients from 6 centres. SF-36 were applied to 51 age-matched healthy controls (HC). Persistent activity for ≥6 months was considered as treatment resistance (r-TAK). The correlation between VDI, clinical characteristics and mental (MCS)/physical (PCS) component scores of SF-36 were analysed. SF-36 and VDI scores were compared between TAK subgroups and HC.RESULTS:The median age, follow-up time and disease duration were 40 (17-68), 60 (6-384), and 72 (6-396) months, respectively. 35% of them were r-TAK. VDI scores (VDIs) in TAK 4 (1-12) were mainly due to the disease itself [4 (1-10)]. VDIs in r-TAK were significantly higher than nr-TAK [5 (2-12) vs. 3 (2-10), p<0.001)]. In the TAK patients, MCS and PCS were found as 43±10 and 38±11, respectively. A high proportion of poor MCS (70%) and PCS (80%) were demonstrated in TAK. A significantly negative but weak correlation was observed between VDI and MCS (p=0.003, r=-0.23), PCS (p<0.001, r=-0.34). Higher VDIs were detected in patients with PCS <50 [5 (1-12) vs. 2 (1-6) p<0.001)]. SF-36 score was significantly lower in TAK than HC.CONCLUSIONS:Disease-related damage mainly caused by peripheral vascular involvement was more predominant than treatment-related damage without reaching the level of severe damage scores, but contributing to poor QoL, in the TAK cohort.

BACKGROUND/PURPOSE:Patients with systemic lupus erythematosus (SLE) have increased rates of cardiovascular disease (CVD) that are one of the major causes of mortality. The aim of this study was to determine the frequencies of metabolic syndrome (MetS) and CVD in SLE patients and investigate the link between these and clinical features of SLE.METHODS:A total of 311 SLE patients were consecutively assessed for cumulative organ damage (SDI/SLICC scores), history of CVD and MetS as defined by the National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III). Clinical data of SLE patients were collected from the records.RESULTS:The mean age of the patients was 40.2 ± 13.4 years and 89% were female. The frequencies of CVD and MetS were 15.2% and 19%, respectively. In this SLE cohort increased age, cumulative damage, disease duration and CVD were associated with MetS. CVD was associated with disease duration, cumulative damage, pericarditis, hematologic involvement, lymphopenia, thrombocytopenia, neurological involvement and antiphospholipid antibody (aPL) positivity. Hydroxychloroquine (HCQ) use was found as a protective factor for CVD.CONCLUSION:In SLE patients, MetS was associated with CVD and both increased with disease duration. Patients who developed MetS and/or CVD had increased cumulative organ damage. Certain clinical features of SLE and the presence of aPL were also associated with CVD. There was a significant protective effect of HCQ from CVD. The prevention of MetS and long-term use of HCQ may be beneficial in improving the prognosis of SLE.

Elaine F. Remmers1, Fulya Cosan2, Yohei Kirino1, Michael J. Ombrello1, Neslihan Abaci3, Colleen Satorius1, Julie M. Le1, Barbara Yang4, Benjamin D. Korman1, Aris Cakiris3, Oznur Aglar3, Zeliha Emrence3, Hulya Azakli3, Duran Ustek3, Ilknur Tugal-Tutkun5, Gulsen Akman-Demir6, Wei Chen7, Christopher I. Amos7, Michael B. Dizon4, Afet Akdag Kose8, Gulsevim Azizlerli8, Burak Erer2, Oliver J. Brand9, Virginia G. Kaklamani10, Phaedon Kaklamanis11, Eldad Ben-Chetrit12, Miles Stanford13, Farida Fortune14, Marwen Ghabra15, William E. R. Ollier16, Young-Hun Cho17, Dongsik Bang18, John O'Shea19, Graham R. Wallace20, Massimo Gadina4, Daniel L. Kastner1, and Ahmet Gül2,3 1 Laboratory of Clinical Investigation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA

The Behçet’s disease (BD)-associated human leukocyte antigen (HLA) allele, HLA-B*51 (B*51), encodes a ligand for a pair of allelic killer immunoglobulin-like receptors (KIR) present on cytotoxic cells—KIR3DL1, which inhibits their cytotoxicity, and KIR3DS1, which activates their cytotoxic activity. We tested whether KIR-regulated mechanisms contribute to BD by testing for association of KIR3DL1/KIR3DS1 genotypes with disease in 1799 BD patients and 1710 healthy controls from Turkey, as well as in different subsets of individuals with HLA-type-defined ligands for the KIR3D receptors. HLA types were imputed from single nucleotide polymorphism genotypes determined with the Immunochip. The presence of inhibitory KIR3DL1 or activating KIR3DS1 alleles did not differ significantly between cases and controls (KIR3DL1: 92.9% vs 93.4%, Pdominant=0.55; KIR3DS1: 42.7% vs 41.0%, Pdominant=0.29). The KIR3DL1/KIR3DS1 alleles were also present at similar frequencies among cases and controls bearing HLA-B with a Bw4 motif; HLA-B with a Bw4 motif with isoleucine at position 80; and HLA-B*51. Our results suggest that pathogenic mechanisms associated with HLA-B*51 do not primarily involve differential interactions with KIR3DL1 and KIR3DS1 receptors. However, due to the complexity of this locus (that is, sequence variation and copy number variation), we cannot exclude a role for other types of KIR variation in the pathogenesis of BD.

Ankylosing spondylitis, psoriasis, and Behcet's disease are seronegative genetically complex diseases that are also considered complex autoinflammatory diseases. These diseases are characterized by strong association of class I human leukocyte antigen (HLA) alleles and also have a strong contribution to disease-risk by variants of the endoplasmic reticulum-associated amino-peptidase 1 (ERAP1) gene that is limited to individuals who carry the disease-specific HLA class I allele. The ERAP1 protein is responsible for trimming peptides for loading onto HLA class I molecules, which are displayed on the surface of nearly all cells, where they play important roles in immune surveillance and in innate and adaptive immune functions. ERAP1 is highly polymorphic with several SNPs encoding variant amino acids that are likely to influence the nature of peptides bound as well as their ability to be trimmed. These non-synonymous coding variants are not found in isolation, but in combinations or allotypes that act in concert to influence the peptidome available for HLA binding and presentation.

Deficiency of adenosine deiminase 2 (DADA2) syndrome is a recently described autosomal recessively inherited autoinflammatory disorder associated with missense mutations in CECR1 gene. Clinical manifestations include early onset stroke, livedoid vascular changes, and a vasculopathy mimicking classical polyarteritis nodosa (cPAN) characterized by microaneurysms and associated inflammatory findings. We herein describe a male patient with homozygous G47R mutation in the CECR1 gene, whose inflammatory findings did not respond to immunosuppressive treatments and recombinant IL-1 receptor antagonist, anakinra injections, but controlled with adalimumab.

QuestionIn Behçet's disease (BD), vasculitis involving blood vessels of nearly all sizes and types may underlie the diverse tissue and organ involvement.Loss of function mutations in the CECR1 gene (encoding adenosine deaminase 2) have recently been shown to cause a recessive genetic disease, deficiency of adenine deaminase 2 (DADA2).Patients with DADA2 exhibit systemic vasculopathy characterized by intermittent fevers, skin rash, and neurovascular manifestations along with other features that can lead to a diagnosis of polyarteritis nodosa.Patients homozygous for the CECR1 p.Gly47Arg mutation are reported in two nonconsanguineous Turkish families and this mutation is found at low frequency in the Turkish population.We therefore attempted to determine whether some BD cases may be explained by adenosine deaminase 2 deficiency and whether this mutation contributes to BD risk in patients of Turkish ancestry. MethodsTurkish BD patients (n = 1,609) and controls (n = 1,519) were genotyped for p.Gly47Arg mutations in the CECR1 gene using a Sequenom assay.The assay interrogated two mutant alleles of the first nucleotide of the Gly47 codon that both encode the glycine to arginine missense change. ResultsWe found p.Gly47Arg mutations in 4 BD patients and 3 healthy controls.No individuals (neither cases or controls) carried two mutant alleles.The carrier frequency for p.Gly47Arg mutations was 0.002 in cases and in controls.

Familial Mediterranean Fever (FMF), the most common form of the hereditary autoinflammatory disorders, is characterized by recurrent attacks of fever along with serosal or synovial inflammation lasting usually 12 to 72 hours. FMF is associated with impaired functional ability, and the persistent disabling features and chronic pain, emotional and physical limitations can have a negative impact on the health-related quality of life (QoL) of the patients. There is no established treatment available for those resistant or intolerant to standard of care colchicine treatment. Interleukin-1 (IL-1) plays a pivotal role in the pathogenesis of crFMF. Canakinumab, a fully human, selective, anti-IL-1β monoclonal antibody, binds to IL-1β and inactivates its signalling activity. Gul et al. have described the efficacy and safety of canakinumab in adults with colchicine resistant (cr) FMF in a local pivotal phase II trial. Here, we report the effect of canakinumab treatment on QoL measured by SF-36 Questionnaire.

Background Avascular necrosis (AVN) in ANCA associated vasculitides (AAV) is a rare finding of damage that has not been investigated in detail in terms of risk factors. Objectives To investigate the prevalance of AVN risk factors in patients with AAV Methods AAV cohort diagnosed according to CHCC, presented with ≥1 organ involvement, being followed-up and treated ≥6 months after diagnosis were included into the study. All symptomatic AVN was demonstrated by MRI. Demographic and clinical data including pre-defined AVN risk factors such as high BMI (≥25), hyperlipidemia, diabetes, smoking status, alcohol intake and cumulative glucocorticoid (GC) exposure were noted into a protocol. Initial BVAS and cumulative VDI were calculated in the majority of cohort. The patients were stratified in accordance to the presence of AVN (AVN+/AVN-). Demographics and AVN risk factors were compared between the groups by using Mann Whitney U test. Results The study group consisted of 129 AAV (16 e-GPA, 28 MPA, 85 GPA) patients (63 female) with the mean age at diagnosis 44±15 and mean follow-up time 60±46.7 (6-182) (med 48). Eighteen of 129 (14%) AAV patients developed AVN (2 MPA, 16 GPA). AVN was observed in knee (2), shoulder (1), hip (14) and ankle (1) and bilateral in 66%. Comparison of the AVN risk factors in AAV patients was shown in Table. Conclusions A very high prevalence of AVN was found in our GPA cohort, which is quite higher than the previously reported frequencies (<1%). However, comparison of GC exposure data could not be done between our preliminary analysis and that of previously reported trial results. Other undefined risk factors to AVN such as variables affecting bone metabolism may contribute to observed differences warranting further investigations. Male gender has been identified as a new risk factor in our cohort, which has to be confirmed in large cohorts. Disclosure of Interest None declared

OBJECTIVES:Takayasu arteritis is a chronic large-vessel vasculitis in young women of reproductive age. We aimed to obtain information on pregnancy in TA retrospectively.METHODS:Takayasu arteritis patients with history of pregnancy were included in this study. The evaluations included physical findings, serum C-reactive protein, erythrocyte sedimentation rate as well as history and symptoms. Information about pregnancies, abortus, deliveries and newborns was obtained from medical records. Disease activity score, disease damage index appraised Kerr's criteria and vasculitis damage index (VDI) and medication were recorded.RESULTS:Thirty-six Takayasu arteritis patients who had a total of 84 pregnancies were evaluated. The mean age of patients ranged 24.5 ± 6.6 years. Subclavian arteries (86%) were the most frequently involved vessels. We were able to complete the follow-up of ten patients who had a pregnancy after diagnosis during the period of pregnancy. Two patients who had renal artery involvement and active disease in third trimester suffered from preeclampsia and a worsening of hypertension. In one of them, disease flared up in the third trimester. There was no active disease in the postpartum sixth month. Maternal heart failure, cerebrovascular accident, death or cerebral hypoperfusion at the time of delivery, asphyxia and newborn anomalies were not seen in any of these patients.CONCLUSIONS:TA pregnancies may have a favourable outcome with regular follow-up schedule and close monitorisation of blood pressure.

Background Increased rate of severe infection (SI) in patients who exposed to immunosuppressive drugs has been a well-known complication in inflammatory rheumatic diseases. However,there are few reports on SI complicating AAV course. Methods We investigated the characteristics of “SI requiring hospitalization” in AAV patients with lung involvement who were previously included into a study evaluating lung damage. Data were collected from hospital records between 2000-2014. Demographics, data on infection investigation including blood, sputum and urine cultures, viral serology, PPD/QTB tests, procalcitonin (PCT), imaging and biopsy findings, comorbidites, vasculitis activity and damage scores, cumulative dose of glucocorticoid (GC), cyclophosphamide (CYC) and rituximab (RTX) were noted into a predefined protocol. Infections that could not be revealed by cultures but succesfully treated with antibiotics were categorized as unidentified (UI). We compared the demographic and clinical data, comorbidities, initial BVAS and cumulative VDI scores and GC/CYC doses according to the presence of SI by Mann-Whitney U test. Results Fifty-one AAV patients with lung involvement (25 female) (40 GPA, 8 MPA, 3 e-GPA) who were diagnosed according to ACR and CHCC criteria were included into the study. Age at diagnosis and duration of follow-up were as follows: 49±13 years (med 51), 67±52 mo (med 47). Lung (100%), kidney (78%), ENT (72%), nervous system (25%) were the involved organs. ANCA positivity was 94% (66% cANCA/anti-PR3, 34% p-ANCA/anti-MPO). Initial BVAS and cumulative VDI scores were 22±7 (4-38) (med 23), 3,4±2,2 (0-9) (med 3), respectively. Twenty-nine relapses occurred in 15 (29%) patients. Cumulative dose of GC and CYC were 16±9 g (med 14), 17±25 (med 6), respectively. RTX was used in 17 patients. Diabetes (18%), chronic kidney failure (25%) were the major comorbidities and 7% had ESRD. Influenza and pneumococcal vaccination and TMP-SMX prophylaxis were applied in one forth and two-thirds of AAV cohort, respectively. Eighty-seven SI noted in 25(52%) patients. Identified and unidentified SI in AAV cohort were shown in Table 1. Recurrent SI occurred in 27% of pulmonary and 33% of non-pulmonary groups. SI was associated with relapse in 16%. Serum PCT level increased in 93% (3.5±16.5, med 0.26) of 33 AAV patients. SI proportion was found to be increased during the first six months (%35) and after the 60th month of follow-up (30%). There were no significant difference between the patients with or without SI according to the risk factors. Four patients died from SI during follow-up. Conclusions Prevalence of SI was high and had a bimodal pattern in the early and late phase of AAV. SI was found to have a high proportion of re-occurrence. SI complicated disease relapses in a small group of patients. Disclosure of Interest None declared

Background Recurrent oral aphthous ulcers are the common manifestation of the Behçet9s disease, and they are indistinguishable from ulcers of recurrent aphthous stomatitis (RAS). There is no reliable biomarker reflecting disease activity in BD, and systemic acute phase reactants are not helpful in evaluation of active disease, especially in patients with predominantly mucocutaneous activity. Objectives We aimed to assess the potential of salivary interleukin-1 alpha and beta (IL-1A and IL-1B) concentrations as well as two S100 proteins, namely S100A12 (calprotectin) and S100A13 in comparison to their serum levels in BD, RAS, and healthy controls. Methods A total of 67 patients with BD, 43 patients with RAS, and 22 healthy controls with no history of aphthous ulcers or other oral mucosal disorders (NA) comprised the study group. BD patients fulfilled the ISG criteria for the diagnosis, and patients with active systemic disease were excluded. Patients with BD and RAS were classified as active and inactive according to the presence or absence of aphthous ulcers at the time of sample collection. Unstimulated saliva and serum samples were collected after overnight fasting. IL-1A, IL-1B, S100A13 and calprotectin levels were measured by ELISA, and concomitant measurements of ESR and serum CRP levels of BD patients were recorded. Results At the time of sample collection, 38 BD patients (18 male, mean age: 39,1±10,3) were classified as active and 29 patients (18 male, mean age: 38,9±10,5) as inactive. Similarly, 19 patients with RAS (11 male, mean age: 36,6±8,7) were active and 24 patients (7 male, mean age: 36,7±10,1) were inactive state. Mean values of salivary and serum ELISA measurements are given in Table 1. Salivary IL-1A and IL-1B levels were higher in BD patients compared to RAS and NA even during inactive state (IL-1A p<0.001 for RAS and p<0.001 for NA, IL-1B p<0.001 for RAS and p=0.003 for NA). There was a correlation between IL-1A and IL-1B levels, but IL-1A increase was more prominent in active BD patients. No correlation was detected between salivary IL-1A and S100A13 levels. Serum CRP and ESR were within normal range in BD patients, and they showed no correlation with salivary measurements. Conclusions These results reveal a role for IL-1A and IL-1B in the development of oral aphthous ulcers, and increased salivary IL-1A levels without an increase in S100A13 levels may suggest pyroptosis or other causes of cellular damage as its source. Further studies are necessary both to improve saliva collection and analysis methods and to search the biomarker potential of salivary IL-1A and IL-1B concentrations in the management of mucocutaneous and systemic manifestations of BD. Acknowledgements There is no conflict of interest. Disclosure of Interest None declared

Background A new histopathological classification was developed to predict renal outcome in AAV nephritis1. Objectives We aimed to investigate the relationship between histopathological findings and renal outcome by using this new classification. Methods Forty-three AAV patients (60% GPA, 40% MPA) diagnosed according to CHCC and followed-up between 2000-2013 and were included into the study. Demographic, clinical and treatment characteristics were recorded into a predefined protocol. Cyclophosphamide and pulse/high dose methylprednisolone was used in remission induction for at least 6 months in all patients. Renal biopsy specimens including ≥10 glomeruli at diagnosis were evaluated by two pathologists (IK, YO) by using new AAV nephritis histopathologic classification. e-GFR at 0, 6th, 12th, 24th, 60th months were calculated with MDRD formula. Mann Whitney U test was used to compare the e-GFR at 0, 6th, 12th, 24th and 60th months within histopathological subgroups. Correlation of the percentage of the normal glomeruli number and the difference between initial and each follow-up e-GFR values in subgroups were tested by Spearman analysis. Results Demographic features of AAV cohort (51% women) were as follows: Mean age at diagnosis was 47,5±14,9 (17-75) (median 49) and total disease duration was 59±41 months (median 53). ANCA testing was positive in 93% (c-ANCA 67%, p-ANCA 27%, c-ANCA/anti-PR3%30, p-ANCA/anti-MPO %14). Kidney was the only involved organ in 25% of cohort. Ten (23%) patients had pulmonary-renal syndrome. Mean disease activity score (BVAS03) was 20±6 (0-38). Four patients died (1 acute renal failure, 1 malignancy, 2 sudden death). The AAV cohort was classified as focal (FS) (37%), crescentic (CS) (40%) and mixed (MS) (23%) subgroups by new classification. No patient was classified for sclerotic subgroup. Median e-GFR values for the histopathologic subgroups during the follow-up visits were shown in figure 1. The focal subgroup demonstrated stable e-GFR values during the follow-up with the highest median e-GFR values in comparison to the other subgroups. Initial e-GFR<15 was found as 53% in the CS. e-GFR was found to be increased significantly between the initial and each follow-up visits in those patients. The MS had an increased e-GFR values, which was became significant 12th and 24th months visits, during the follow-up. Only CS showed a positive correlation between the percentage of the number of normal glomeruli and the e-GFR changes during the first 2 years, but it was not statistically significant. Conclusions The focal category according to the new histopathological classification was found to have a better renal outcome in this small group of AAV nephritis cohort, as reported in the literature. Three-forth of the patients, who underwent hemodialysis at the time of diagnosis were in the CS. A significant increase of e-GFR was demonstrated with the standard immunosuppressive treatment in the active patients. Renal function showed a trend towards an increase in accordance with the percentage of the normal glomeruli in the CS. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4882

Background Behçet's disease (BD) is a multisystemic inflammatory disease mainly characterized by recurrent oral aphthae, genital ulcers, ocular and skin lesions. Although genetic factors, infectious agents and immunological mechanisms have all been implicated, pathogenesis of BD still remains to be elucidated. Correlation of clinical findings with acute phase response is usually considered poor, and there is no established biomarker for monitoring disease activity in BD patients. Objectives This study aimed to analyze the correlation of serum levels of different acute phase reactants with the clinical activity of BD, by measuring ESR, CRP, SAA, IL-8, S100A12, and also S100A13, which plays a key role in the non-classical release of IL-1α. Methods A group of 95 patients with BD (58 male, 37 female), 18 patients with familial Mediterranean fever (FMF), 22 healthy subjects were enrolled to the study. Among BD patients, 31 had an active disease with overt manifestations during the first sampling, and a second serum sample was collected from 24 after their clinical activity was controlled. A group of 32 BD patients had no manifestations for at least 6 months, and named as patients in remission, and 8 had only recurrent oral aphthous ulcers. All FMF samples were collected during an acute attack. Serum levels of CRP and SAA were measured by nephelometry and of S100A13, S100A12 (Cusabio Biotech, China) and IL-8 (BD Bioscienses, USA) by ELISA. The study protocol was approved by the local ethics committee, and all participants gave written informed consent. Results The mean values ESR, CRP, SAA and IL-8 were significantly higher in active BD patients with manifestations compared to the values of patients with no manifestations (n=46, including inactive and remission patients) (43.7 vs 14.6, 36.2 vs 1.8, 133 vs 6.9, 28.5 vs 29.4, respectively) and to the values of the healthy controls (16.5, 1.65, 4.4 and 16.3, respectively). Analysis of paired samples of 24 patients during active and inactive periods also showed significant decrease of ESR, CRP, SAA, and IL-8 with the controlled activity (38 vs 14.2, 26.6 vs 2.1, 44.5 vs 6.8, 58.5 vs 7.8, respectively, P<0.001). Addition of patients with only oral ulcers to the active patients did not change the significant results, except IL-8. Patients with additional manifestations had significantly higher CRP values than patients with only oral ulcers. High (greater than mean + 2SD of healthy controls) S100A12 values were observed in 34% of active patients, and this proportion reduced to 5% with the decreased disease activity. Serum S100A13 values were below the detection level in all groups. In FMF patients, all acute phase reactants but IL-8 were higher than active patients with BD. Conclusions This study reveals dynamic changes of acute phase reactants in parallel with disease activity in BD patients. The level of those elevations may reflect the total area of inflammatory lesions. Considering the magnitude of changes along with manifestations, serum CRP and SAA levels can be used for the monitoring of clinical manifestations and treatment responses of patients with BD. Acknowledgements Supported by: Istanbul University, Scientific Research Projects Coordination Unit, IUBAP No: 2012/23482. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5998