Ilana Kaufman

Prevalence of TNF-α Blocker Immunogenicity in Psoriatic Arthritis

Objective. The longterm use of tumor necrosis factor (TNF)-α blockers is limited by the formation of neutralizing antibodies. To the best of our knowledge, immunogenicity in psoriatic arthritis (PsA) has not been investigated in depth. Our objective was to evaluate the prevalence and significance of TNF-α blocker immunogenicity in PsA. Methods. Consecutive patients with PsA treated with either infliximab (IFX), adalimumab (ADA), or etanercept (ETN) > 3 months participated in our cross-sectional study. Their demographic and clinical characteristics, skin and joint disease activity, and records of use of methotrexate (MTX) and other medications were collected. Drug levels (ELISA) and antidrug antibodies (ADAb; Bridging ELISA) were evaluated before the next injection or infusion. Results. A total of 93 patients with PsA were recruited (48 receiving ADA, 24 IFX, and 21 ETN), with a mean age of 53 years (range 21–83 yrs), composed of 53% women. One-fourth of the patients were concomitantly treated with MTX. Altogether, 77% of the patients demonstrated therapeutic drug levels. High levels of ADAb were found in 29% of patients taking ADA, 21% taking IFX, and 0% taking ETN. ADAb significantly correlated with lower drug levels, higher 28-joint Disease Activity Scores, and higher global assessments. MTX use correlated significantly with a lower prevalence of ADAb. Conclusion. Significant levels of ADAb were present in up to 29% of patients with PsA treated with ADA or IFX. ADAb clearly correlated with low therapeutic drug levels and higher disease activity variables. The use of MTX significantly decreased ADAb prevalence, and its use should be strongly considered in combination with TNF-α blocker antibodies in patients with PsA.

Cardiac dysfunction in patients with systemic lupus erythematosus and antiphospholipid syndrome

Objective: To comparatively assess the parameters of systolic and diastolic cardiac function in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Methods: Consecutive patients (n = 74) who were free of cardiovascular symptoms were divided into four groups: (1) SLE (n = 23); (2) SLE with antiphospholipid antibodies (aPL; n = 18); (3) SLE with APS (n = 20); and (4) primary antiphospholipid syndrome (PAPS; n = 13). Pulsed, continuous, colour Doppler echocardiography, and M-mode and B-mode studies were performed. Results: Left ventricular end diastolic and end systolic dimensions were higher in SLE as compared with patients with PAPS (p = 0.022 and 0.022, respectively), with a trend towards a lower fractional shortening in SLE (p = 0.07), suggesting systolic dysfunction. Parameters of diastolic function were more impaired in patients with APS, reflected by lower left ventricular and right ventricular E wave to A wave (E:A) ratios in patients with APS (groups 3, 4) compared with those without APS (groups 1, 2; 1.15 (0.40) v 1.49 (0.43), p = 0.001 and 1.19 (0.31) v 1.49 (0.41), p = 0.001, respectively) and a more prolonged left ventricular isovolumic relaxation time (IVRT; 94.2 (24.6) v 84.4 (17) ms, respectively, p = 0.055). Patients with APS were older than those without APS (47.12 (14.86) v 34.29 (12.6), p = 0.0001). Patients with SLE were younger than those with PAPS (38.19 (14.68) v 48.53 (13.97), p = 0.023). Conclusion: Abnormal echocardiographic findings were detected frequently in asymptomatic patients with SLE or PAPS. Although patients with SLE were younger, left ventricular systolic function was more impaired in patients with SLE compared with those with PAPS, whereas left ventricular and right ventricular diastolic function, as reflected by IVRT and E:A ratios, were significantly more impaired in patients with APS.

The Effect of the Presence of Fibromyalgia on Common Clinical Disease Activity Indices in Patients with Psoriatic Arthritis: A Cross-sectional Study

Objective. To study the effect of the presence of fibromyalgia (FM) on common clinical disease activity indices in patients with psoriatic arthritis (PsA). Methods. Seventy-three consecutive outpatients with PsA (mean age 51.7 yrs; 42 females, 57.5%) were enrolled in a prospective cross-sectional study. FM was determined according to American College of Rheumatism criteria (2010 and 1990). All patients underwent clinical evaluation of disease activity and completed the Health Assessment Questionnaire (HAQ), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Dermatology Life Quality Index, and the Leeds Enthesitis Index (LEI). Disease activity was evaluated using the Composite Psoriatic Disease Activity Index (CPDAI), minimal disease activity (MDA), and the Disease Activity Index for Psoriatic Arthritis (DAPSA) scores. Results. The overall prevalence of FM was 17.8% (13 patients), and all but 1 were women (12 patients, 92.3%, p = 0.005). CPDAI and DAPSA scores were significantly higher in patients with coexisting PsA and FM (9.23 ± 1.92 and 27.53 ± 19.23, respectively) than in patients with PsA only (4.25 ± 3.14 and 12.82 ± 12.71, respectively; p < 0.001 and p = 0.003). None of the patients with FM + PsA met the criteria for MDA, whereas 26 PsA-only patients did (43.3%, p = 0.003). HAQ, BASDAI, and LEI scores were significantly worse in patients with PsA and associated FM. Conclusion. Coexisting FM is related to worse scores on all tested measures in patients with PsA. Its influence should be taken into consideration in the treatment algorithm to avoid unnecessary upgrading of treatment.

Longterm Efficacy of an Antipneumococcal Polysaccharide Vaccine among Patients with Autoimmune Inflammatory Rheumatic Diseases.

Objective. To estimate the longterm humoral response of an antipneumococcal polysaccharide vaccine (PPSV23) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or inflammatory bowel disease (IBD)-associated spondyloarthropathy (SpA), and the effect of demographic and clinical factors and treatment on the longterm efficacy of the vaccine. Methods. A total of 145 consecutive patients treated with biologics [tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) receptor inhibitors] or methotrexate (MTX) participated in this study. Fifteen were excluded because of absent information regarding their vaccination status (n = 9) or because of technical problems in obtaining their serum sample (n = 6). They were diagnosed with RA (n = 63, 48.5%), PsA (n = 29, 22.3%), AS (n = 28, 21.5%), or IBD-associated SpA (n = 3, 2.3%). Their mean age was 54.6 years, and 61.5% were women. Data were collected on the timing of vaccination, demographic and clinical characteristics, and treatment, and patients’ serum antipneumococcal antibody levels were tested. Results. Two-thirds of the patients (67.7%) had received PPSV23 45 months (mean) earlier. Treatment included TNF-α inhibitors (73.9%), IL-6 receptor inhibitors (13.1%), or MTX without a biological treatment (13%). The uptake of vaccination was significantly higher in the older population (> 65 yrs). Vaccinated patients had significantly higher antibody levels compared with vaccine-naive patients. The antibody levels had been preserved after 10 years. MTX use, but not biologics, was associated with significantly lower antibody levels. Conclusion. The longterm efficacy of the PPSV23 vaccination seems to be preserved among patients with RA, PsA, AS, and IBD-associated SpA for at least 10 years. Efficacy is slightly impaired by MTX, but it is not affected by biologics. These findings suggest that revaccination after 5 years might not be needed for all, and testing the antibody titers should be considered to identify those who may benefit from revaccination.

Expression levels of selected genes can predict individual rheumatoid arthritis patient response to tumor necrosis factor alpha blocker treatment

Abstract Objectives: Rheumatoid arthritis (RA) patients have many therapeutic options; however, tools to predict individual patient response are limited. The Genefron personal diagnostic kit, developed by analyzing large datasets, utilizes selected interferon stimulated gene expressions to predict treatment response. This study evaluates the kit’s prediction accuracy of individual RA patients’ response to tumor necrosis alpha (TNFα) blockers. Methods: A retrospective analysis was performed on RA patients reported in published datasets. A prospective analysis assessed RA patients, before and 3 months after starting a TNFα blocker. Clinical response was evaluated according to EULAR response criteria. Blood samples were obtained before starting treatment and were analyzed utilizing the kit which measures expression levels of selected genes by quantitative real time polymerase chain reaction (PCR). ROC analysis was applied to the published datasets and the prospective data. Results: The Genefron kit analysis of retrospective data predicted the response to a TNFα blocker in 53 of 61 RA patients (86.8% accuracy). In the prospective analysis, the kit predicted the response in 16 of 18 patients (89% accuracy) achieving a EULAR moderate response, and in 15 of 18 patients achieving a EULAR good response (83.3% accuracy). ROC analysis applied to the two published datasets yielded an AUC of 0.89. ROC analysis applied to the prospective data yielded an AUC of 0.83 (sensitivity – 100%, specificity – 75%) The statistical power obtained in the prospective study was .9. Conclusion: The diagnostic kit predicted the response to TNFα blockers in a high percentage of patients assessed retrospectively or prospectively. This personal kit may guide selection of a suitable biological drug for the individual RA patient.

AB0138 Interferon-gamma challenge of PBMC from patients with lupus nephritis in remission decreases suppressor of cytokine signaling 1 (SOCS1) and regulatory t cells (TREGS) and promotes immune activation

Background Interferon-gamma (IFN-γ) plays an important role in the development of lupus nephritis (LN). Regulation of IFN-γ signaling that occurs in disease remission and in active LN is herein addressed. Objectives To study the impact of IFN-γ on PBMC obtained from patients with LN in remission as compared to active LN. Methods Sixteen patients fulfilling the ACR classification criteria for systemic lupus erythematosus were recruited. All patients had a history of LN of whom 10 were in remission (as defined by EULAR criteria) and 6 had active LN (as defined by SLEDAI-2K or BILAG). Healthy subjects (n=10) were included as a control group. Sera and PBMC were obtained from each individual. Flow cytometry, western blots and real time RT-PCR were used in processing and detection of cell subtypes, protein and mRNA levels. Recombinant human IFN-γ (rhIFN-γ) and anti-IFN-γ neutralizing antibody were used in vitro. Mann-Whitney and student t-tests were used for statistical analysis. Results In active LN there was a significant 2-fold increase in CD4+CD69+ activated T cells as compared to healthy subjects and patients in remission. Reactivity to interferon-gamma receptor was determined by the phosphorylation of its predominant transcription factor, signal transducer and activator of transcription 1 (STAT1) in the cells that were incubated with rhIFN-γ or with media alone. In active LN, 3- and 6-fold increase in pSTAT1 occurred with rhIFN-γ incubation during 24h and 48h, respectively, and healthy subjects responded likewise. In patients in remission, pSTAT1 increase was even higher (by 8- and 10-fold at 24h and 48h, respectively). After 24h incubation with rhIFN-g all groups had elevated (mRNA) expression of SOCS1, but at 48h, it significantly decreased in healthy subjects and in patients in remission by 34% and 50%, respectively. Further, at 24h the frequency of CD4+CD127lowFoxP3+ regulatory T cells (e.g. Tregs) increased by 27–30% in active LN and in healthy subjects, and in remission it was minimally changed. At 48h, the frequency of Tregs significantly decreased in healthy subjects (to baseline levels before rhIFN-γ challenge) and in patients in remission (by 24%, p=0.003). A challenge of PBMC from LN patients in remission with sera (at 1% concentration) derived from patients with active LN resulted in 7.5-fold increase in pSTAT1 expression and 20–30% decrease in Tregs, however, combination of sera and anti-IFN-g neutralizing antibody resulted in 5-fold decrease in pSTAT1 expression and significantly diminished the decrease in Tregs. Conclusions In LN in remission a challenge with IFN-γ could lead to immune activation and a risk of flare-up, as it results in a decrease in both SOCS1 and Tregs and a robust STAT1 phosphorylation. In active LN, STAT1 phosphorylation is less diminishing, as both SOCS1 and Tregs are saturated, which could affect their suppressive effectiveness. Disclosure of Interest None declared

FRI0679 Whole spine and SIJ MRI of psoriatic arthritis patients: descriptive study of the spine, and sacroiliac joints involvement in a cross sectional large cohort

Background Detection of axial disease has important implications. Data on the structural changes of the spine and SIJ in PsA is mainly based on plain XR and MRI of SIJ. The prevalence and distribution of spinal changes in PsA as detected by MRI is largely unknown. Objectives To evaluate acute and structural changes in spine and SIJ by whole spine MRI performed in a consecutive clinical cohort of PsA. Methods Adult PsA (CASPAR criteria) patients were enrolled in the study. All underwent clinical exam, CRP, HLA-B27 tests, and MRI of the entire spine and SIJ. Spinal sagittal T1-W, STIR and semi-coronal T1-W and T2-W with fat saturation sequences of the SIJ were performed. The spine was scored for the presence of syndesmophytes, bone marrow edema (BME)/fatty corners and enthesitis. SIJS were scored (Berlin score) for the presence of BME, fatty replacement, erosions, sclerosis, and ankylosis. Findings were further categorized into active sacroiliitis (ASAS1), structural sacroiliitis, and spinal findings compatible with SpA (≥3 BME or ≥4 fatty corners2). All MRIs were evaluated by an experienced musculoskeletal radiologist, blinded to clinical data. Data were analyzed by SPSS Version 20.0. Results Ninety six patients completed the study.(Table1) Active/structural/total sacroiliitis was detected in 26%/11.5%/37.5% of patients, respectively. Spinal SpA was demonstrated in 15.6%.(Table 2) Isolated spinal changes were detected in 2.1% of the cohort. Presence of inflammatory back pain (IBP) by ASAS correlated with the prevalence of active sacroiliitis (p 0.024) and SpA (axial/SIJ) (p 0.003). The extent of psoriasis severity (PASI) correlated with both SIJ and whole spine SpA changes. (p 0.02 for both) Gender differences or biologic therapy did not affect the prevalence of SIJ or spine involvement.Table 1. Demographic and clinical data Age (mean, yr) 50±13 Gender M:F 50:46 Psoriasis/PsA duration (mean, yr) 19±13.6/9±8 PASI 3.9±8.9 ASDAS-CRP 2.2±1 Back pain (%)/Inflammatory back pain by ASAS (%) 70%/30% HLA-B27 (%) 4.4% Current DMARD Tx (%)/Current biologic Tx (%) 45%/35%Table 2. Whole spine MRI findings N (%) patients Active Inflammatory Lesions  ≥1 BME corner 22 (23%)  ≥1 posterior elements enthesitis 4 (4%) Structural Lesions  ≥1 corner erosion 10 (10.4%)  ≥1 fatty corner 30 (31%)  ≥1 syndesmophytes 30 (31%) Distribution of inflammatory lesions:  Cervical 2.1%, Thoracic 18.8%, Lumbar 14.6% Distribution of structural lesions:  Cervical 10.4%, Thoracic 32.3%, Lumbar 25% Conclusions In the present PsA cohort, active and structural sacroiliitis was more prevalent vs typical spinal SpA changes. In particular, there was a paucity of SpA changes in the cervical spine. The most prominent axial findings included fatty corners and syndesmophytes. IBP presence and extensive skin disease correlated with SpA axial and SIJ changes. References Lambert RG. Ann Rheum Dis. 2016,75. Hermann KG. Ann Rheum Dis 2012.71. Disclosure of Interest None declared

AB0440 The fine line between takayasu and giant cell arteritis: a retrospective study

Background Takayasu arteritis (TAK) and Giant cell arteritis (GCA) are classified as two different vasculitides.[1] The differentiation is based on age at onset (under 40y for TAK, above 50y for GCA) and vascular distribution (aorta and its primary branches for TAK and mainly extracranial arteries for GCA). However, both diseases involve large vessels and share histopathology findings. Objectives Our goal is to describe a series of patients above the age of 50y with large vessel arteritis and vascular involvement typical of TAK. Methods Eighteen Patients (median age 64y, 16 females) were selected from 3 centers in Israel. A retrospective review of the cases was preformed with special emphasis on clinical characteristics (including clinical course and outcome), laboratory values and vascular involvement. Vascular imaging by CT angiography, MRI angiography or planar angiography was done in all cases. Results Five patients fulfilled the ACR criteria for GCA, 5 the ACR criteria for TAK, 3 both GCA and TAK criteria, while 5 patients had clear involvement of large vessels without fulfilling the criteria for either disease. The dominant presenting symptoms were constitutional, while only a few patients had cranial or peripheral symptoms. On physical examination, 61% had signs of vascular compromise including: blood pressure arm differences, non palpable limb pulses or vascular bruits. All patients had elevated acute phase reactants, 78% had anemia. Temporal artery biopsy showed giant cell arteritis in 6 out of 9 biopsies. The majority (78%) showed either involvement of the ascending aorta, the aortic arch, descending aorta or a combination of these. The distribution of vessel involvement was as following: carotid arteries in 9 patients, subclavian arteries in 12, axillary arteries in 5, abdominal aorta in 9, mesenteric or celiac trunk in 7, renal arteries in 3, iliac arteries in 7 and femoral arteries in 2. All the patients were treated with prednisone and 50% with steroid sparing drug. Nine out of 15 patients (60%) that have completed at least 1 year of follow-up achieved remission. Three additional patients had a partial remission. Three patients of the remission group relapsed. A comparison between the patients who fulfilled the ACR criteria for GCA and those who fulfilled for TAK showed that the first group was slightly older (70y vs. 64y) and had more constitutional symptoms while the second group had more peripheral symptoms and more vascular involvement signs in physical examination. The acute phase reactants were slightly higher in the GCA group. However, no substantial differences in the distribution of vascular involvement, type of treatment or outcome measures were observed. Conclusions Vascular involvement typical of TAK in patients above the age of 50y with large vessel arteritis seems to be more frequent than previously assumed. The differences between those who fulfill the criteria for each disease are minor. Our findings support the assumption that TAK and GCA represent a spectrum of the same disease. References Fries JF, Hunder GG, Bloch DA, et al. The ACR 1990 criteria for the classification of vasculitis. Arthritis Rheum. 1990;33:1135-6. Disclosure of Interest None Declared