Extra-skeletal manifestations in axial spondyloarthritis are associated with worse clinical outcome despite the use of TNF blocking therapy

Objective To investigate the prevalence and 4-year incidence of acute anterior uveitis (AAU), inflammatory bowel disease (IBD) and psoriasis, and to explore associations of newly developed extra-skeletal manifestations (ESMs) with clinical disease outcome in a large cohort of axial spondyloarthritis (SpA) patients. Methods All consecutive patients included in the Groningen Leeuwarden Axial SpA (GLAS) cohort between 2004 and 2011 were analysed. History of ESMs at baseline and newly developed ESMs during 4-year follow-up were only recorded when diagnosis by an ophthalmologist, gastroenterologist or dermatologist was present. Results Of the 414 included axial SpA patients, 31.5% had a positive history of one or more ESMs: 24.9% AAU, 9.4% IBD, and 4.4% psoriasis. History of psoriasis was significantly associated with more radiographic damage, especially of the cervical spine. Of the 362 patients with 4-year follow-up data, 15.7% patients developed an ESM: 13.3% patients with AAU, of which 3.6% had a first episode and 9.7% had recurrent AAU, 1.9% developed IBD, and 0.8% developed psoriasis. Patients who newly developed ESMs (without history of ESMs) had worse ASQoL score (mean 10.0 vs. 5.9, p=0.001), larger occiput to wall distance (median 6.3 vs. 2.0, p=0.021) and more limited modified Schober test (mean 12.6 vs. 13.6, p=0.014) after 4 years of follow-up. The majority of patients developing an ESM used anti-TNF therapy. Conclusion History of ESMs was present at baseline in one-third of axial SpA patients. The 4-year incidence of ESMs was relatively low, but patients who developed a new ESM reported worse quality of life.

POS0034 RADIOGRAPHIC ENTHESEAL LESIONS AT HIP AND PELVIC REGION ARE ASSOCIATED WITH LONGER DISEASE DURATION, HIGHER BMI AND MORE SEVERE SPINAL AND HIP RADIOGRAPHIC DAMAGE IN PATIENTS WITH ANKYLOSING SPONDYLITIS

Background:Enthesitis is an important feature of ankylosing spondylitis (AS) and structural and inflammatory entheseal lesions (EL) are frequently present on ultrasound. Plain radiographs also provide good imaging of structural entheseal involvement1. Until now, little is known about the presence of structural EL at the hip and pelvic region and the association with patient characteristics in AS.Objectives:Our aim was to investigate the prevalence of radiographic EL at the hip and pelvic region in AS patients compared to age and sex matched control subjects and to explore the relation with AS patient characteristics.Methods:AS patients from the Groningen Leeuwarden Axial SpA (GLAS) cohort, included between November 2004 and December 2010, with available anteroposterior (AP) pelvis radiographs at baseline were included. All patients fulfilled the modified New York criteria for AS. Additionally, 100 randomly selected AP pelvis radiographs from age and sex matched control subjects were obtained from the radiology department of the University Medical Center Groningen. The sacroiliac joints of all radiographs were blinded and radiographs were scored independently by two trained observers unaware of patient characteristics and treatment. The entheseal sites scored were: trochanter major, trochanter minor, os ischium, crista iliaca, both left and right side. The following 3 EL were scored: erosion/cortical irregularity, calcification and enthesophyte. Only lesions with absolute agreement between both observers were used for analyses. Radiographic spinal involvement was scored according to the modified Stoke AS Spine Score (mSASSS; range 0-72) and radiographic hip involvement according to the Bath AS Radiology Index (BASRI)-hip (range 0-4). Independent samples t test, Mann-Whitney U test, Chi-Square test, and Fisher Exact test were used to compare patient characteristics between patients with and without radiographic EL.Results:Of the 167 included AS patients, 117 (70%) were male, mean age was 43 ± 11 years, 133 (80%) were HLA-B27 positive and median symptom duration was 16 years (range 1-53). 127 (76%) AS patients and 58 (58%) controls showed EL, with 501 lesions in total of which 377 (75%) in AS patients. AS patients showed significantly more lesions than controls at all 5 locations. Os ischii showed the most lesions in both AS patients and controls (66% vs 53%, p<0.05). The most prevalent type of lesion in both groups was erosion/cortical irregularity (72% vs 51%, p<0.005). Enthesophytes were also more often observed in AS patients than in controls (31% vs 21%, p=0.07). Prevalence of calcifications was low in both groups and not significantly different (5% vs 2%, p=0.22). AS patients with EL were significantly older (mean 45.2 vs 35.1 yrs, p<0.005) and had longer symptom duration (median 18 vs 7.5 yrs, p<0.005) than patients without EL. Furthermore, patients with BMI >25 had significantly more often enthesophytes (42% vs 16%, p<0.05) than patients with a normal BMI. Additionally, AS patients with EL had significantly more often radiographic spinal damage than patients without EL with median mSASSS total score 8.7 vs 1.0 (p<0.005) and a trend toward significance for radiographic hip involvement (BASRI-hip score ≥2; p=0.06).Conclusion:Radiographic EL at hip and pelvic region are significantly more prevalent in AS patients than in age and sex matched controls. AS patients with EL were significantly older, had longer symptom duration and more spinal radiographic damage than patient without EL. Furthermore, BMI >25 was associated with a higher prevalence of enthesophytes. These new findings contribute to the knowledge of entheseal involvement in AS.References:[1]Voudouris et al. J Musculoskelet Neuronal Interact. 2003;3(1):89-100.Disclosure of Interests:Freke Wink Consultant of: Abbvie, Thomas Diemel: None declared, Suzanne Arends: None declared, Anneke Spoorenberg Consultant of: Abbvie, Pfizer, MSD, UCB, and Novartis, Grant/research support from: Abbvie, Pfizer, UCB and Novartis.

POS1036 COLLAGEN TURNOVER MARKERS ARE ASSOCIATED WITH ACTIVE PSORIATIC ARTHRITIS AND DECREASE WITH GUSELKUMAB TREATMENT IN A PHASE-3 CLINICAL TRIAL

Background:Guselkumab (GUS), an interleukin-23p19-subunit monoclonal antibody, demonstrated efficacy compared to placebo (PBO) in reducing skin and musculoskeletal signs and symptoms in patients with active psoriatic arthritis (PsA) in two phase-3 studies, DISCOVER-1 & -2, and in retarding structural damage in DISCOVER-2.1,2Objectives:To evaluate tissue-derived extracellular matrix (ECM) products3,4 in serum of PsA patients in the DISCOVER-2 study and their relationship with radiographic damage, clinical response, and impact of treatment.Methods:In DISCOVER-2, patients were treated with GUS 100 mg at Week (w) 0, 4, then every 8w (q8w); GUS 100 mg every 4w (q4w); or matching PBO. At w24, PBO patients were crossed over to GUS q4w. A total of 11 serum biomarkers of ECM collagen formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4, and PRO-C6) and degradation (C1M, C2M, C3M, C4M, C6M, and COL10) were measured (by Nordic Bioscience) in a subset of 260 patients from the DISCOVER-2 program at Weeks 0, 4, 24, & 52 and in 76 healthy controls matched for age, sex, and ethnicity. PsA patients were selected randomly, though enriching for subjects with greatest radiographic changes, at Weeks 24 and 52. Significance defined by p<0.05 and |fold difference| ≥1.25.Results:At baseline, collagen degradation markers C1M, C3M, C4M, C6M and collagen formation markers PRO-C3 and PRO-C6 were significantly higher in the serum of PsA patients compared to matched healthy controls. Baseline C3M, C4M, and C6M were positively correlated to baseline skin and joint disease; baseline C1M, C3M, C4M, C6M, and PRO-C1 were positively correlated to baseline radiographic damage (data not shown). Levels of C1M (a maker indicating breakdown of collagen type I, the major collagen subtype in the bone) were significantly decreased after 24w treatment with GUS (Figure 1), reaching significant differences from placebo with the GUS 100 mg q4w group. For the PBO patients who crossed over to GUS at w24, there was also a reduction in this marker observed at w52 (Figure 1). In patients treated with GUS or PBO, there were no significant differences in baseline expression levels of the analytes in responders (patients achieving ACR20 at w24) compared with non-responders. However, ACR20 responders in the combined GUS group had a significantly greater reduction in C1M levels compared to non-responders (p=0.0065) at w24.Conclusion:This work provides evidence that collagen biomarkers in serum are dysregulated in patients with PsA compared to healthy controls, and that GUS impacts levels of these proteins. Importantly, C1M serves as a biomarker that tracks with joint response. We observed a greater reduction in C1M in ACR responders compared to non-responders, providing insight into how GUS may be working to protect from degradation of bone in PsA.References:[1]Deodhar A et al. Lancet 2020;395:1115-1125[2]Mease PJ et al. Lancet 2020;395:1126-1136[3]Gudmann NS et al. Clin Exp Rheumatol 2017;35:653-659[4]Sardar S et al. Annals of the Rheum Dis 2019;78(Suppl 2): https://ard.bmj.com/content/78/Suppl_2/867.1Disclosure of Interests:Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Roche, UCB, Consultant of: AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Roche, UCB, Matthew J Loza Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Arumugam Palanichamy Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Oliver FitzGerald Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Consultant of: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Christopher T. Ritchlin Speakers bureau: AbbVie, Amgen, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB, Frederic Baribaud Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Kristen Sweet Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC.

OP0253 STRUCTURAL DAMAGE IN AXIAL SPONDYLOARTHRITIS: IS THERE A PREFERRED WAY TO ASSESS PROGRESSION OVER TIME?

Background:Axial spondyloarthritis (axSpA) is characterized by development of structural damage in the spine, assessed by conventional radiographs (CR). The modified Stokes Ankylosing Spondylitis Scoring System (mSASSS) includes all the SpA-relevant CR findings and is the most frequently used scoring system for quantification of spinal structural damage in patients (pts) with axSpA. Radiographic progression over 2 years using mean mSASSS progression, scored by a blinded ‘paired’ (sets of CRs of the same patient) approach, is considered as a key treatment outcome reflecting structural progression in clinical trials. However, this approach has been accompanied by questions about the influence of pts showing mSASSS ‘improvement’, indicating possible disappearance of syndesmophytes over time, something ‘naturally unexpected’.Objectives:To investigate the performance of mSASSS in assessing spinal radiographic damage and progression in axSpA pts using different approaches of CR evaluations.Methods:Complete sets (cervical and lumbar CRs) from the German SpA Inception Cohort (GESPIC) at baseline and after 2 years were blinded to all clinical and demographic characteristics and then scored using the mSASSS by 5 different experienced readers, 2 blinded and 3 unblinded to the timepoint of CR performance. The final mSASSS score was calculated as a mean of 2 (blinded) or 3 (unblinded) readers. Descriptive statistics, cumulative probability plots and shift analyses (agreement of 2/2 readers in the blinded and 2/3 readers in the unblinded group) were performed for each reader group.Results:A total of 210 pts (mean age 37.3y, 51% male, 79% HLA-B27+) with non-radiographic (n=115) and radiographic (n=95) axSpA at baseline were included. The mean mSASSS at baseline was 4.3±8.3 vs. 3.4±7.9, while the mean progression was 0.7±2.3 vs.1.0±1.9 mSASSS units for the blinded vs. the unblinded group, respectively (Figure). On the patient level, progression of ≥2 mSASSS units was found in 30 (14.3%) vs. 37 (17.6%) pts in the blinded vs. the unblinded group, while agreement between groups was seen in 179 (85.2%) pts, 18 (8.9%) pts for progression and 161 (76.7%) for no progression.Figure 1.Cumulative probability plot for mean mSASSS scores (all scores) in blinded (A) and unblinded (B) and ‘definite’ scores in blinded (C) and unblinded (D) scoring approachIn the analysis of ‘definite’ CR findings (only scores of 2=syndesmophytes or 3=ankylosis), the mean mSASSS score at baseline was 3.3±8.0 vs. 2.6±7.2 and the mean radiographic progression was 0.6±2.4 vs. 0.8±2.1 mSASSS units for the blinded vs. the unblinded group, respectively (Figure). On the patient level, progression was found in 37 (17.6%) vs. 33 (15.7%) pts in the blinded vs. the unblinded group, while agreement between groups was seen in 188 (89.5%) pts, 24 (11.3%) for progression and in 164 (78.1%) pts for no progression.In the shift analysis, mSASSS worsening was found in 35 (0.8%) and mSASSS ‘improvement’ in only 4 (0.1%) out of a total of 4.373 vertebral edges (VE) analyzed in the blinded and in 109 (2.2%) and 2 (0.04%), respectively, out of a total of 4.914 VE analyzed in the unblinded group (Table). The majority of progression was found for the development of ‘definite’ signs of progression in both the blinded (25/35, 71.4%) and the unblinded (61/109, 56%) group, while more VE showing ‘minor’ (only scores of 1=sclerosis, squaring, erosion) signs of progression were found in the unblinded (48/109, 44%) vs. to the blinded (10/25, 28.6%) group.Conclusion:Despite lower mean baseline mSASSS, higher mean mSASSS progression was found using the unblinded approach, while in the shift analysis the unblinded approach was also more specific, confirming the absence of ‘improvement’ of radiographic damage over time. These results were similar in the analysis on the patient’s level. The scoring approach and the influence of ‘minor’ radiographic changes should be taken into account for avoiding the so-called ‘background noise’ in the evaluation of mSASSS.Acknowledgements:GESPIC was initially supported by the BMBF. As a consequence of the funding reduction by BMBF according to schedule in 2005 and stopped in 2007, complementary financial support has been obtained also from Abbott, Amgen, Centocor, Schering–Plough, and Wyeth. Starting from 2010, the core GESPIC cohort was supported by AbbVie.Table 1.Shift analysis of the blinded and unblinded reading approach on the basis of VE.Disclosure of Interests:None declared

OP0255 THE ROLE OF PELVIC MORPHOLOGY IN AXIAL SPONDYLOARTHRITIS

Background:Axial Spondyloarthritis (axSpA) is a chronic inflammatory disease affecting the axial skeleton. It includes non-radiographic axSpA and radiographic axSpA [Ankylosing Spondylitis (AS)]. Male axSpA patients often have greater damage, while women report a higher disease burden. The role of pelvic morphology in the axSpA phenotype has not been explored. There is anatomic sexual dimorphism between the male and female pelvis. Given the phenotypic gender differences in axSpA, the role of pelvic morphometry is of interest.Objectives:The purpose of this study is to determine whether an association exists between pelvic dimensions and radiographic damage in patients with axSpA, as well as to compare these measurements in axSpA patients and healthy controls.Methods:This was a cross-sectional analysis comparing axSpA cases from a prospective cohort and non-axSpA controls from the UCSF radiology databank. Informed consent was obtained from axSpA cohort patients and this study was approved by the institutional IRB. To be included in the analysis, we limited inclusion to age ≤ 50 with an Anterior Posterior (AP) pelvis radiograph in the system. We excluded non-nulliparity, pelvic fracture history, BMI ≥ 30kg/m2, any prosthetic history and avascular necrosis. We measured the pelvic inlet, pelvic outlet, and subpubic angle (based on validated scoring methods) (Figure 1) and assessed its relation to sacroiliac joint (SIJ) damage (average SIJ score, New York criteria) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) in cases. AxSpA patients were also compared to age/gender matched controls. Pelvic measurements were performed by 2 blinded independent-trained readers in randomized, blinded image order. Inter-rater reliability was assessed. When examining the relationship between pelvic measurements and damage, linear regression was used to stratify by gender and adjust for potential confounders.Results:The axSpA cohort included 481 patients, of which 210 men and 89 women were included in this analysis and gender/age matched controls. Rater inter-class correlation was above 0.70 for pelvic outlet and above 0.80 for other measures. Cases and controls were similar (Table 1). The regression analysis showed a significant relationship between the sub-pubic angle and damage in the spine (coeff=-0.342, p=0.003) in men with axSpA. A sensitivity analysis, excluding mSASSS outliers (mSASSS ≥ 16) upheld the relationship (coeff=-1.40, p=0.002).Conclusion:In men with axSpA, there appears to be a relationship between sub-pubic angle and spinal radiographic damage. This is consistent with our finding that women have larger sub-pubic angles and lower spinal radiographic damage than men. A greater sub-pubic angle may protect against spinal involvement or associate with other protective factors. Further work should be performed to understand the contribution of pelvic anatomy to damage in axSpA.Disclosure of Interests:Ethan Zaccagnino: None declared, Rina Patel: None declared, Lianne S. Gensler Consultant of: AbbVie, Eli Lilly, Gilead, Novartis, Pfizer and UCB., Grant/research support from: Pfizer and UCB.

Prognostic Factors for Radiographic Progression in Patients with Seronegative Rheumatoid Arthritis

(1) Background: It has long been suggested that seronegative rheumatoid arthritis (RA) represents a clinical entity quite distinct from that of seropositive. However, analytical studies of seronegative RA dedicated to clinical outcomes regarding radiographic progression and related risk factors are scarce. The aim of this study is to evaluate radiographic outcome and prognostic factors for radiographic progression in patients with seronegative rheumatoid arthritis. (2) Methods: Subjects included RA patients reported as seronegative for both rheumatoid factor and anti-citrullinated protein antibody, who were treated at Jeju National University Hospital in South Korea between 2003 and 2016, including follow-up of at least 2 years. All patients fulfilled 1987 ACA or 2010 ACR/EULAR RA criteria. Radiographic progression was measured by yearly change in the Sharp van der Heijde (SvdH) score during follow-up periods. Medical records, laboratory and radiographic data were retrospectively analyzed, and linear regression analysis was performed to evaluate prognostic factors for radiographic progression in patients with seronegative rheumatoid arthritis. (3) Results: In total, 116 patients with seronegative RA were observed and 43 (37.1%) patients demonstrated radiographic damage during follow-up period. Mean age at diagnosis was 48 years and 86 (74.1%) patients were female. Symptom duration at diagnosis was 1.3 years and mean follow-up duration was 5.2 years. Patients with radiographic damage at diagnosis were 14 (12.1%) and mean SvdH score was 6.8 at diagnosis. Radiographic damage and SvdH at diagnosis significantly correlated with radiographic progression in patients with seronegative RA after adjusting age, sex, symptom duration, number of active synovitis, and CRP at diagnosis (β-coefficient 6.5 ± 1.84; p = 0.001 and β-coefficient 0.12 ± 0.02; p < 0.001, respectively). (4) Conclusions: This study determined that radiographic damage and SvdH at diagnosis were predictive factors in progression of radiographic damage in patients with seronegative rheumatoid arthritis. A large comparative study dedicated to this issue in seronegative RA is required.

Predictive value of anti-CarP and anti-PAD3 antibodies alone or in combination with RF and ACPA for the severity of rheumatoid arthritis

Objectives The objective of this study was to analyse the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies, alone or in combination with RF and ACPA, to identify patients at high risk of developing severe RA outcomes. Methods Patients within the Swiss Clinical Quality Management registry with a biobank sample were tested for RF, ACPA, anti-CarP, and anti-PAD3 antibodies. We examined the association of each autoantibody with DAS28, HAQ and radiographic damage (Ratingen) at baseline and longitudinally. Results Analyses included 851 established RA patients and 516 disease controls [axial spondyloarthritis (axSpA = 320) and PsA (196)]. Anti-CarP and anti-PAD3 antibodies were, respectively, present in 22.4% and 10.7% of the whole RA population, and in 13.2% and 3.8% of the RF and ACPA double seronegative patients. At baseline, RA patients with anti-PAD3 had higher DAS28 (4.2 vs 3.7; P= 0.005) and significantly more radiographic damage (14.9 vs 8.8; P= 0.02) than anti-PAD3-negative patients. In the ACPA-negative subgroup, baseline Ratingen scores were significantly higher in anti-PAD3-positive patients (P= 0.01). The combination of anti-PAD3, RF IgM, and ACPA was associated with significantly higher baseline radiographic scores than the double seropositive group (P= 0.04). The presence of any two of the previous autoantibodies was associated with significantly greater radiographic progression over 10 years than if all were absent (P= 0.02). There were no differences in RA outcome measures with regards to anti-CarP. Conclusions Anti-PAD3 antibodies are associated with higher disease activity and joint damage scores in RA patients.

Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis

Background Circulating IgA anti-citrullinated protein antibodies (ACPA) associate with more active disease, but a previous study implied that salivary IgA ACPA is related to a less severe disease. Therefore, we aimed to characterize the IgA ACPA response in the saliva and serum in relation to clinical picture and risk factors among patients with rheumatoid arthritis (RA). Methods RA patients (n = 196) and healthy blood donors (n = 101), included in the cross-sectional study “Secretory ACPA in Rheumatoid Arthritis” (SARA), were analyzed for ACPA of IgA isotype, and for subclasses IgA1 and IgA2 ACPA in paired saliva and serum samples using modified enzyme-linked immunosorbent assays (ELISA) targeting reactivity to a cyclic citrullinated peptide (anti-CCP). Cutoff levels for positive tests were set at the 99th percentile for blood donors. Antibody levels were related to clinical characteristics, radiographic damage, smoking habits, and carriage of HLA-DRB1/shared epitope (SE). Results IgA ACPA in the saliva was found in 12% of RA patients, IgA1 occurred in 10%, and IgA2 in 9%. In serum, IgA ACPA was found in 45% of the patients, IgA1 in 44%, and IgA2 in 39%. Levels of IgA ACPA in the saliva correlated significantly with serum levels of IgA (r = 0.455). The presence of salivary IgA ACPA was associated with a higher erythrocyte sedimentation rate (ESR), 28-joint disease activity score, tender joint count, and patient global assessment at the time of sampling. None of the antibodies was associated with smoking, SE, or radiographic damage. Conclusion Salivary IgA ACPAs were detected in a subset of RA patients in association with higher disease activity. This suggests that mucosal ACPA responses in the oral cavity may contribute to disease-promoting processes in RA.