Abstract: Observational cohort studies have shown that there is low, but still detectable progression level in radiographic sacroiliitis, which might also have an impact on the function in patients with axial spondyloarthritis (axSpA). Recent data showed that tumor necrosis factor inhibitors (TNFi) might retard spinal progression when initiated earlier and taken longer in patients with axSpA. However, the question of whether they also have such an effect on radiographic progression in sacroiliac joints (SIJs) is still unclear. Objectives: To investigate the longitudinal association between radiographic sacroiliitis progression and treatment with TNFi in patients with early axial SpA in a long-term inception cohort. Methods: Based on the availability of at least two sets of SIJ radiographs, 301 patients (166 with nr-axSpA, symptom duration ≤5 years and 135 with r-axSpA, symptom duration ≤10 years) from the German Spondyloarthritis Inception Cohort (GESPIC) were included in this analysis. These patients contributed with a total of 737 2-year radiographic intervals. Two trained and calibrated central readers scored the radiographs according to the modified New York criteria. If both scored an image as definite radiographic sacroiliitis, the patient was classified as having r-axSpA. The sacroiliac sum score was calculated as a mean of both readers. The association between previous as well as current TNFi use and radiographic sacroiliitis progression, which was defined as the change in the sacroiliitis sum score over 2 years, was analysed using longitudinal generalized estimating equations (GEE) analysis. Results: At baseline, 9 (3.0%) patients were treated with a TNFi, and 87 (28.9%) patients received at least one TNFi during the entire follow-up period. A total of 141 of the radiographic intervals were covered with TNFi of any duration, while 109 of them were covered with a TNFi of at least 12 months. While receiving ≥12 months TNFi in the previous interval was associated with a lower progression of the sacroiliitis sum score compared to not receiving TNFi in the previous interval, this was not the case in patients who received TNFi ≥12 months in the current 2-year interval (Figure 1). The significant association between TNF ≥12 months in the previous interval and progression in the sacroiliitis sum score were confirmed in the adjusted multivariable longitudinal GEE analysis. In addition, a similar trend for the beneficial effects was observed in different models, which included other treatment definitions with TNFi in the previous 2-year interval (Table). Table 1. The longitudinal GEE analysis of the association between progression in the sacroiliitis sum score and TNFi use. TNFi treatment definition Reference β* (95% CI ) TNFi for ≥ 12 months in the previous 2-year interval No TNFi for ≥ 12 months in the previous 2-year interval -0.09 (-0.18, -0.003 ) Any TNFi use in the previous 2-year interval No TNFi use in the previous 2-year interval -0.09 (-0.17, 0.002) TNFi for ≥ 12 months in the current 2-year interval No TNFi for ≥ 12 months in the current 2-year interval -0.03 (-0.11, 0.06) Any TNFi use in the current 2-year interval No TNFi use in the current 2-year interval 0.05 (-0.05, 0.14) TNFi for ≥ 12 months in the previous and ≥ 12 months in the current 2-year interval No TNFi for ≥ 12 months in the previous and ≥ 12 months in the current 2-year interval -0.08 (-0.17, 0.004) * Parameter estimates from the multivariable models adjusted for sex , age at the beginning of the current 2-year interval, HLA-B27 positivity, symptom duration at the beginning of the current 2-year interval, time-averaged elevated CRP , time-averaged BASDAI , and time-averaged NSAID intake score in the current 2-year interval. Conclusion: Treatment with TNFi was associated with retardation of radiographic sacroiliitis progression in patients with axSpA. This effect becomes evident between 2 and 4 years after treatment initiation. References: 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. Disclosure of Interests: Murat Torgutalp: None declared, Valeria Rios Rodriguez: None declared, Maryna Verba: None declared, Mikhail Protopopov: None declared, Fabian Proft: None declared, Judith Rademacher: None declared, Hildrun Haibel: None declared, Martin Rudwaleit Consultant of: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma, Joachim Sieper: None declared, Denis Poddubnyy Speakers bureau: AbbVie, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Biocad, Gilead, GlaxoSmithKline, Eli Lilly, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, MSD, Novartis, and Pfizer

Abstract: Crohn’s disease (CD) and ulcerative colitis (UC) are grouped as inflammatory bowel disease (IBD), and both are frequently found as extra-musculoskeletal manifestations in spondyloarthritis (SpA). Several studies have described the connection between SpA and IBD in both directions. Still until today, no studies have investigated possible differences in the musculoskeletal manifestations between the two main entities of inflammatory bowel disease: CD and UC. Objectives To evaluate the clinical characteristics associated with the presence of CD or UC in patients with spondyloarthritis from the international cross-sectional ASAS-perSpA study. Methods We analyzed 3152 patients from the ASAS per-SpA cohort who had a diagnosis of axial SpA or peripheral SpA according to the treating rheumatologist. Patients with IBD - confirmed by endoscopy - were identified and stratified by CD or UC. Patients in which their IBD disease was not specified, were excluded. Demographics, clinical characteristics, treatments and patient-reported outcomes were compared between both subgroups. Results Among the 146 patients diagnosed with IBD from the 3152 patients included in the analysis, 87 (59.6%) presented with CD (75 patients with axial SpA and 12 with peripheral SpA) and 39 (26.7%) with UC (34 patients with axial SpA and 5 with peripheral SpA) - Figure 1. A total of 20 (13.7%) patients with IBD were excluded, due to an inconclusive diagnosis of IBD. Patients with CD and UC had similar age (44.9 vs 44.0 years old) and sex distribution, although a slightly higher frequency of males was observed in CD than UC (63.2% vs 51.3%). The diagnostic delay for SpA was 7.0 years for CD and 8.1 years for UC. We did not find differences between both groups related to any musculoskeletal manifestations such as chronic back pain, uveitis, arthritis, enthesitis or dactylitis (Table 1). The only parameter showing a significant difference between CD and UC was the Bath Ankylosing Spondylitis Functional Index (BASFI) with a mean score of 3.3 vs 2.2 respectively (p=0.02) (Table 1). CD patients showed a higher tendency to be HLA-B27 positive (51.9% in CD vs. 39.4% in UC), but this did not reach statistical significance. No differences were observed regarding treatment patterns between both groups. Table 1. Demographics and clinical characteristics related to spondyloarthritis of patients with concomitant Crohn’s disease or ulcerative colitis (n=146). Crohn’s Disease N=87 Ulcerative Colitis N=39 P Age, mean (SD) 44.9 (13.5) 44.0 (13.0) 0.68 Sex, n/N (%) male 55/87 (63.2) 20/39 (51.3) 0.21 Smoker ever, n/N (%) 36/87 (41.4) 19/39 (48.7) 0.44 Diagnostic delay of SpA (years), mean (SD) 7.0 (6.9) 8.8 (8.1) 0.38 Psoriasis ever, n/N (%) 9/87 (10.3) 6/39 (15.4) 0.47 Uveitis ever, n/N (%) 17/87 (19.5) 11/39 (28.2) 0.28 Synovitis ever, n/N (%) 42/87 (48.3) 18/39 (46.2) 0.83 Enthesitis ever, n/N (%) 26/87 (29.9) 14/39 (35.9) 0.50 Dactylitis ever, n/N (%) 3/87 (3.4) 1/39 (2.6) 0.79 Axial involvement ever (according to the rheumatologist), n/N (%) 79/87 (90.8) 37/39 (94.9) 0.44 Sacroiliitis on X-ray, n/N (%) 64/87 (73.6) 26/39 (66.7) 0.19 HLA-B27 positive, n/N (%) 28/54 (51.9) 13/33 (39.4) 0.26 CRP mg/L, mean (SD) 11.1 (33.8) 15.3 (30.1) 0.13 ASDAS-CRP, mean (SD) 2.4 (1.0) 2.4 (1.1) 0.84 BASFI, mean (SD) 0-10 3.3 (2.6) 2.2 (2.1) 0.02 csDMARDs ever, n/N (%) 71/87 (81.6) 35/39 (89.7) 0.25 bDMARDs ever, n/N (%) 72/87 (82.8) 33/39 (84.6) 0.80 ASDAS, Ankylosing Spondylitis Disease Activity Score; BASFI, Bath Ankylosing Spondylitis Functional Index; bDMARD, biological disease-modifying antirheumatic drugs; CRP, c-reactive protein; csDMARD, conventional synthetic disease-modifying antirheumatic drugs; SD, standard deviation; SpA, spondyloarthritis. Conclusion In our ancillary analysis of the ASAS-perSpA study in patients with SpA and concomitant CD or UC, no differences in the clinical presentation or demographic characteristics between the two subgroups were observed, except for the BASFI. Disclosure of Interests None declared

Abstract: There is some evidence that NSAIDs, in particular celecoxib (CEL), might possess not only symptomatic efficacy but also disease-modifying properties in radiographic axial spondyloarthritis (r-axSpA) formerly known as ankylosing spondylitis, retarding progression of structural damage in the spine if taken continuously. For biological disease-modifying antirheumatic drugs (bDMARDs), retardation of structural damage progression has also been demonstrated, but at least 4 years of treatment seem to be necessary (at least for tumour necrosis factor inhibitors – TNFi) to see such an effect. Therefore, a combination of an NSAID with a TNFi might bring additional benefits in terms of retardation of structural damage progression especially in high-risk patients. Objectives The aim of this RCT was to evaluate the impact of treatment with the COX-II-selective NSAID (CEL) when added to a TNFi (golimumab - GOL) compared with TNFi (GOL) alone on progression of structural damage in the spine over 2 years in patients with r-axSpA. Methods Eligible patients had r-axSpA and high disease activity (BASDAI ≥4), NSAID failure and risk factors for radiographic spinal progression: C-reactive protein 〉 5 mg/l and/or ≥1 syndesmophyte(s). The trial consisted of two phases: a 12-week run-in phase, in which all included patients received treatment with GOL 50 mg every 4 weeks sc, followed by a 96-week controlled treatment period, in which patients who achieved a BASDAI improvement of ≥2 points were randomly assigned to GOL + CEL 200 mg bid or GOL alone arms. The primary endpoint was radiographic spinal progression as assessed by the change in the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) after 108 weeks in the intent-to-treat population, read by 3 independent readers blinded for the treatment arm and the time-point. Results Of the 157 screened patients, 81.5% (n=128) were enrolled into the run-in phase. 109 patients fulfilled the BASDAI response criterion at w12 and were randomized 1:1 (54 vs. 55) to GOL+CEL or GOL alone; 97 (45 vs. 52) patients completed the study at w108. Clinical characteristics of the randomized patients are shown in Tab. 1. The mSASSS change after w108 was 1.1 (95%CI 0.2; 2.0) vs. 1.7 (95%CI 0.8; 2.6) in the GOL+CEL vs. GOL alone groups, respectively, p=0.79. Figure 1 shows the cumulative probability of the mSASSS change in both treatment arms. New syndesmophytes in the opinion of three readers occurred in 11% vs. 25% of the patients in the GOL+CEL vs. GOL alone groups, respectively, p=0.12. During the study, a total of 14 serious adverse events (SAE) were reported (7 in the GOL+CEL group, 5 in the GOL alone group and 2 during the run-in phase). Figure 1. Cumulative probability plot of mSASSS progression over 108 weeks of treatment. Conclusion In this study, a combined therapy with GOL+CEL did not show significant superiority over GOL monotherapy in retarding radiographic spinal progression over two years in r-axSpA patients. However, the observed numerical reduction in radiographic spinal progression associated with the combined treatment might be, however, clinically relevant for patients at high risk for progression. Table 1. Baseline characteristics of randomized patients Parameters GOL+CEL N=54 GOL alone N=55 All patients N=109 validn value validn value validn value Sex, male n (%) 54 40 (74.1) 55 41 (74.5) 109 81 (74.3) Age, years Mean (SD) 54 39.9 (9.9) 55 37.5 (10.8) 109 38.7 (10.4) Smoker n (%) 53 19 (35.8) 55 22 (40) 108 41 (38) HLA-B27 positivity n (%) 54 45 (83.3) 51 47 (92.2) 105 92 (87.6) BASDAI Mean (SD) 54 6.2 (1) 55 6.1 (1.1) 109 6.1 (1.1) BASMI Mean (SD) 54 2.6 (1.9) 54 2.9 (1.4) 108 2.8 (1.6) CRP 〉 5 mg/L n (%) 54 38 (70.4) 55 38 (69.1) 109 76 (69.7) ASDAS-CRP Mean (SD) 54 3.6 (0.6) 55 3.7 (0.9) 109 3.7 (0.8) Prior bDMARDs n (%) 54 17 (31.5) 55 9 (16.4) 109 26 (23.9) Presence of ≥ 1 syndesmophyte(s) n (%) 54 27 (50) 55 28 (50.9) 109 55 (50.5) mSASSS Mean (SD) 54 13.5 (16.9) 55 10.3 (13.2) 109 11.9 (15.2) Acknowledgements The CONSUL study has been supported by a grant from the German Ministry of Education and Research (BMBF), grant number FKZ 01KG1603 and study medication (golimumab) was provided free of charge by MSD Sharp & Dohme GmbH, Munich, Germany. Furthermore we would like to thank Anne Weber, Bianca Mandt, Claudia Lorenz, Hildrun Haibel, Judith Rademacher, Laura Spiller, Petra Tietz as well as all participating rheumatologist and included patients. Disclosure of Interests Fabian Proft Speakers bureau: AMGEN, AbbVie, BMS, Celgene, Janssen, MSD, Novartis, Pfizer, Roche, UCB, Consultant of: Novartis, Grant/research support from: Novartis, UCB, Lilly, Burkhard Muche Speakers bureau: UCB Pharma, AMGEN, Consultant of: UCB Pharma, AMGEN, Valeria Rios Rodriguez Speakers bureau: AbbVie, Falk e.V., Murat Torgutalp: None declared, Mikhail Protopopov Consultant of: Novartis, Joachim Listing: None declared, Maryna Verba: None declared, Uta Kiltz: None declared, Jan Brandt-Juergens: None declared, Maren Sieburg: None declared, Swen Holger Jacki: None declared, Joachim Sieper Speakers bureau: AbbVie, Janssen, Merck, Novartis, Consultant of: Abbvie, Janssen, Lilly, Merck, Novartis, UCB, Denis Poddubnyy Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Biocad, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Eli Lilly, MSD, Novartis, and Pfizer.

Abstract: There are conflicting data regarding effect of nonsteroidal anti-inflammatory drugs (NSAID) on radiographic spinal progression in axial spondyloarthritis (axSpA). The analysis of the first 2-year of the GErman SPondyloarthritis Inception Cohort (GESPIC) showed that higher NSAID intake may retard new bone formation in r-axSpA. It remained, however, unclear, whether cyclooxygenase-2 selective inhibitors (COX2i) might have a stronger effect than non-selective (NS) ones and if the effect could be observed also in nr-axSpA. Objectives To investigate the effect of NSAIDs (COX2i and NS) intake on radiographic spinal progression in patients with r-axSpA and nr-axSpA. Methods Based on availability of at least two sets of spinal radiographs during 10-year follow-up, 243 patients with early axSpA (130 and 113 nr- and r-axSpA, respectively) from GESPIC were included in this analysis. The patients contributed a total of 540 2-year radiographic intervals. Radiographs were scored by 3 trained and calibrated readers according to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Final mSASSS was calculated as a mean of 3 readers, and progression was defined as absolute mSASSS change score over 2 years. NSAID type, daily dose, and frequency of intake were recorded at visits. The ASAS index of NSAID intake (0-100) counting both dose and duration of intake was calculated for intervals. The association between NSAID intake (NSAID type and NSAID score) and radiographic spinal progression over 2 years was analysed using longitudinal generalized estimated equations (GEE). Results At baseline, 161 (66.3%) patients were treated with NSAIDs. While 289 (53.5%) and 128 (23.7%) 2-year radiographic intervals were covered by NS and COX-2i respectively, 123 (22.8%) intervals were not covered by NSAID. The significant association between higher NSAID intake and retardation of radiographic spinal progression was found in adjusted multivariable longitudinal GEE analysis. This effect was mostly attributable to patients with r-axSpA (Table 1). mSASSS progression was numerically lower in patients taking COX2i (irrespectively of dose) as compared to patients treated with NS-NSAIDs; in stratified analysis, however, there was no clear dose-dependency (as reflected by NSAID index) in both groups (Figure 1, Table 1). Table 1. The association between radiographic spinal progression (mSASSS change score) and NSAID intake in patients with axSpA in multivariable longitudinal GEE All axSpA β (95% CI )* (n=461 ) nr-axSpA β (95% CI )* (n=244 ) r-axSpA β (95% CI )* (n=217 ) NSAID intake score, per 10 points -0.04 (-0.09, 0.00 ) -0.02 (-0.06, 0.02) -0.07 (-0.13, 0.00 ) NSAID type §  NS inhibitors vs No NSAID 0.30(-0.07, 0.66) 0.25(-0.07, 0.57) 0.26(-0.40, 0.92)  COX2i vs No NSAID 0.17(-0.19, 0.54) 0.15(-0.15, 0.46) 0.18(-0.49, 0.85)  COX2i vs NS inhibitors -0.12(-0.37, 0.12) -0.10(-0.28, 0.09) -0.08(-0.57, 0.40) Analysis stratified according to NSAID type Non-selective NSAID intake score, per 10 points -0.06(-0.12, 0.00) -0.04(-0.09, 0.01) -0.07(-0.17, 0.03) COX2 selective NSAID intake score, per 10 points -0.06(-0.13, 0.02) -0.03(-0.07, 0.02) -0.09(-0.18, 0.01) axSpA: axial spondyloarthritis; COX2i, cyclooxygenase-2 selective inhibitors; n, number of current 2-year radiographic intervals in multivariable analyses; NS, non-selective COXi; NSAID, non-steroidal anti-inflammatory drugs. *All multivariable models were adjusted for sex, symptom duration at the beginning of the interval, time-averaged ASDAS the interval, classification as radiographic axSpA, smoking in the interval, mSASSS at the beginning of theinterval, and TNFi use in the interval. §NSAID intake score was added in this model. Conclusion Higher NSAID intake is associated with lower radiographic spinal progression, particularly in r-axSpA patients. COX2i might possess a stronger inhibitory effect on radiographic progression as compared to NS-NSAIDs. Disclosure of Interests Murat Torgutalp: None declared, Valeria Rios Rodriguez Consultant of: AbbVie, Grant/research support from: Falk e.V, Ani Dilbaryan: None declared, Fabian Proft Speakers bureau: Novartis, Lilly, UCB AbbVie, AMGEN, BMS, Hexal, MSD, Pfizer, Roche and Janssen, Grant/research support from: Novartis, Lilly and UCB, Mikhail Protopopov Consultant of: Novartis and UCB, Maryna Verba: None declared, Judith Rademacher Consultant of: Novartis and UCB, Hildrun Haibel Consultant of: Boehringer, Janssen, MSD, Novartis, Sobi, Roche, Pfizer, AbbVie, and Sobi, Joachim Sieper Speakers bureau: Abbvie, Janssen, Lilly, Merck, Novartis, UCB, Consultant of: AbbVie, Lilly, Merck, Novartis, UCB, Martin Rudwaleit Speakers bureau: AbbVie, Boehringer Ingelheim, Celgen, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, UCB., Consultant of: AbbVie, Boehringer Ingelheim, Celgen, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, UCB., Denis Poddubnyy Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, and UCB., Consultant of: AbbVie, Biocad, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Eli Lilly, MSD, Novartis, Pfizer.

Abstract: There are inconclusive data on the effect of tumor necrosis factor inhibitors (TNFi) on radiographic spinal progression in axial spondyloarthritis (axSpA). Although inflammation and new bone formation are linked in axSpA, TNFi failed to show inhibition of radiographic spinal progression over two years compared to historical cohorts in pivotal studies in radiographic axSpA. Subsequent observational studies suggested that a longer treatment duration, earlier treatment initiation and effective inflammation suppression might be required to achieve inhibition of radiographic progression. Objectives: The aim of the current study was to evaluate the effect of TNFi on radiographic spinal progression in patients with early axSpA in a long-term inception cohort. Methods: A total of 266 patients with early axSpA (with r-axSpA with symptom duration ≤10 years and nr-axSpA with symptom duration ≤5 years) from the German Spondyloarthritis Inception Cohort (GESPIC) with at least two sets of spinal radiographs obtained at least 2 years apart during a 10-year follow-up were included. These patients contributed with a total of 542 2-year radiographic intervals. Spinal radiographs were evaluated by three trained and calibrated readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The final mSASSS was calculated as a mean of three reader scores. The association between the current TNFi, previous TNFi and radiographic spinal progression defined as the absolute mSASSS change score over 2 years was analyzed using longitudinal generalized estimating equations (GEE) analysis. Results: Only 9 patients were treated with a tumor necrosis factor inhibitor (TNFi) at baseline, and a total of 77 patients received TNFi during the entire follow-up period that gave 103 2-year intervals covered by TNFi of any duration, and 78 intervals covered by TNFi with treatment duration of at least 12 months. Radiographic spinal progression in axSpA patients receiving TNFi in the current 2-year interval was not different from progression in patients not treated with TNFi, while TNFi in the previous 2-year interval was associated with lower progression compared to patients without TNFi in this interval (Figure 1). The latter was also evident for patients who received TNFi in both previous and current 2-year intervals, i.e. patients treated with TNFi over 4 years. The longitudinal GEE analysis confirmed no significant association between current TNFi treatment and radiographic spinal progression but a significant association between TNFi in the previous 2-year interval (especially if this was continued also in the current interval giving 4 years in total) and the progression in the current one (Table 1). Table 1. The association between the change of the mSASSS over two years and current and/or previous treatment with TNFi in the longitudinal generalized estimation equation analysis. TNFi treatment definition Reference β* (95% CI ) TNFi for ≥12 months in the previous 2-year interval TNFi for ≥12 months in the current 2-year interval Yes No TNFi for ≥12 months in the current 2-year interval -0.19 (-0.56 to 0.18) Yes No TNFi for ≥12 months in the previous 2-year interval -0.56 (-0.95 to -0.17 ) Yes Yes No TNFi for ≥12 months in the current and previous 2-year intervals -0.59 (-1.03 to -0.15 ) *Parameter estimates from the multivariable models adjusted for sex, symptom duration at the beginning of the current 2-year interval, time-averaged ASDAS in the current 2-year interval, smoking in the current 2-year interval, classification as non-radiographic or radiographic axSpA, and mSASSS at the beginning of the current 2-year interval. Conclusion: TNFi treatment exhibits a time-shifted inhibitory effect on radiographic spinal progression in axSpA that becomes evident only in the second 2-year interval after treatment initiation. Acknowledgements: GESPIC was initially supported by the BMBF. As 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. Disclosure of Interests: Denis Poddubnyy Speakers bureau: AbbVie, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Biocad, Gilead, GlaxoSmithKline, Eli Lilly, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Valeria Rios Rodriguez: None declared, Murat Torgutalp: None declared, Ani Dilbaryan: None declared, Maryna Verba: None declared, Fabian Proft: None declared, Mikhail Protopopov: None declared, Judith Rademacher: None declared, Hildrun Haibel: None declared, Joachim Sieper: None declared, Martin Rudwaleit Consultant of: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma

Abstract: Previous studies showed that patients with non-radiographic and radiographic axial spondyloarthritis (nr- and r-axSpA) have similar disease burden and similar response to anti-inflammatory therapy given similar level of inflammatory activity. Only little is known, however, about long-term disease course in patients with early axSpA. Objectives: To investigate the long-term (up to 10 years) clinical course of patients with early axSpA. Methods: In total, 525 patients with early axSpA (r-axSpA with symptom duration ≤10 years and nr-axSpA with symptom duration ≤5 years) from the German Spondyloarthritis Inception Cohort (GESPIC) were included. The final patient classification was based on central reading results in 458 patients with available pelvic X-rays, and on local rheumatologist judgement in 67 patients. A total of 251 patients were finally classified as r-axSpA and 274 as nr-axSpA. Clinical evaluation, which included disease activity (BASDAI, C-reactive protein – CRP, ASDAS) as well as therapy recording, was performed at baseline and every 6 months thereafter until year 2 and annually thereafter till year 10. Treatment was conducted at the discretion of the local rheumatologist. Results: Since the cohort has started prior to introduction of TNF inhibitors (TNFi), only 2% patients received TNFi at baseline that increased to 23% at year 10 (15% in nr-axSpA and 31% in r-axSpA) – Figure 1. The use of NSAIDs and csDMARDs decreased in both groups (Figure 1), while use of systemic steroids did not change substantially (9% at baseline, 8% at year 10). The proportion of patients with low disease activity according to BASDAI ( 〈 4) was higher in r-axSpA as compared to nr-axSpA at almost all time points, while the proportion of patients with low disease activity according to ASDAS ( 〈 2.1), as well as with ASDAS inactive disease ( 〈 1.3) was similar between nr-axSpA and r-axSpA (Figure 2). In the group of patients who completed year 10 (n=134 in total, 68 with nr-axSpA, 67 with r-axSpA) the same trends in therapy and disease activity were observed. Conclusion: Patients with nr-axSpA and r-axSpA showed a similar disease course in terms of disease activity on the group level. The drop-out rate in this observational cohort was overall high, but comparable between groups. The lower proportion of patients with nr-axSpA being treated with TNFi might reflect a later introduction of TNFi for this indication. Acknowledgments: GESPIC has been financially supported by the German Federal Ministry of Education and Research as well as by Abbott, Amgen, Centocor, Schering–Plough, and Wyeth. From 2010 till 2019 GESPIC has been supported by Abbvie. Disclosure of Interests: Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Valeria Rios Rodriguez Consultant of: Abbvie, Novartis, Murat Torgutalp: None declared, Maryna Verba: None declared, Johanna Callhoff: None declared, Mikhail Protopopov Consultant of: Novartis, Fabian Proft Grant/research support from: Novartis Pharma GmbH, Consultant of: Consultancy / speaker fees from: Abbvie, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: Consultancy / speaker fees from: Abbvie, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Judith Rademacher: None declared, Hildrun Haibel Consultant of: Abbvie, Jansen, MSD, and Novartis, Speakers bureau: Abbvie, Jansen, MSD, and Novartis, Joachim Sieper Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Speakers bureau: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Martin Rudwaleit Consultant of: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma

Abstract: Vitamin D deficiency has been shown to be associated with higher disease activity and severity of several inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and spondyloarthritis (SpA). It is, however, unknown if vitamin D level might affect the response to treatment with biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients with SpA. Objectives To investigate the association between vitamin D serum levels and the response to a bDMARD therapy in patients with axial SpA. Methods Patients with a radiographic axial SpA (r-axSpA), fulfilling the modified New York criteria and starting a bDMARD therapy were recruited between 2015 and 2019 in an extension of the prospective German Spondyloarthritis Inception Cohort (GESPIC-AS). All patients were required to have at inclusion high disease activity (BASDAI 〉 =4 and/or ASDAS 〉 =2.1) despite previous treatment with nonsteroidal anti-inflammatory drugs. Demographics, patient clinical characteristics and vitamin D serum levels were collected at baseline. Disease activity measures (BASDAI, CRP, ASDAS) were assessed at baseline and after 6 months of bDMARD treatment. Vitamin D deficiency was defined as serum level of 25-hydroxyvitamin D 〈 20 ng/mL. A multivariable regression analysis was performed to determine the association between vitamin D serum level at baseline and the treatment response as defined by BASDAI and ASDAS change scores at month 6 as compared to baseline. Results A total of 129 patients with r-axSpA were included in the study. No patient took supplements of vitamin D at baseline. Patients had an average age (mean±SD) of 36.5±10.5 years, 64.3% were males and 86.6% were HLA-B27 positive. The prevalence of vitamin D deficiency in our cohort was 54.3%. Patient characteristics and disease activity were comparable with regard to the presence of vitamin D at baseline (Table 1); with the exception of body mass index (BMI), which was higher in patients with vitamin D deficiency. In the multivariable linear regression analysis, baseline serum level of vitamin D was independently and significantly associated with higher change in BASDAI and ASDAS (Figure 1). Table 1. Baseline characteristics of patients with radiographic axial SpA (n=129) according to vitamin D levels at baseline. Patients with vitamin D deficiency ( 〈 20 ng/mL)n=70 Patients with normal levels of vitamin Dn=59 Age, years 36.6±11.0 36.3±10.0 Male sex 46 (65.7) 37 (62.7) BMI, kg/m 2 26.0±4.5* 24.0±3.8 Smoking, ever 41 (58.6) 29 (49.2) Winter and Spring, n (%) 33 (47.1) 23 (39.0) Symptom duration, years 11.5±11.3 10.3±7.1 HLA-B27 positive 62 (88.6) 50 (84.7) Uveitis ever 17 (24.3) 12 (20.3) Psoriasis ever 11 (15.7) 7 (11.9) IBD ever, n (%) 2 (2.9) 7 (11.9) CRP, mg/L 12.9±19.3 13.9±15.3 BASDAI 5.7±1.4 5.4±1.4 ASDAS 3.4±0.8 3.5±0.8 BASFI 4.6±2.2 4.4±1.9 BASMI 3.1±1.5 2.7±1.3 NSAID intake, current 50 (71.4) 45 (76.3) DMARDs intake, ever 9 (12.9) 6 (10.2) TNFi naive 55 (78.6) 47 (79.7) Corticoids intake, current 5 (7.1) 2 (3.4) *p value 〈 0.05. All numerical variables were presented as mean±SD, all categorical variables were presented as n (%). BMI, body mass index; CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug; IBD, inflammatory bowel disease; NSAID, nonsteroidal anti-inflammatory drug; TNFi, tumor necrosis factor inhibitor. Figure 1. Association between the response to bDMARDs (change in BASDAI and ASDAS after 6 months) and level of vitamin D at baseline in patients with radiographic axial SpA in the multivariable regression analysis. Conclusion Higher vitamin D levels at baseline may predict a better treatment response to bDMARDs in patients with r-axSpA. It has to be shown, however, if vitamin D supplementation might result in a better treatment response in axial SpA. Disclosure of Interests None declared

Abstract: Magnetic resonance tomography (MRI) plays a key role in the early diagnosis of axial spondyloarthritis (axSpA). However, the detection of changes indicative of axSpA requires specific expertise, which poses a challenge to non-specialized centers. Deep learning (an advanced machine learning method) based on training an artificial neural network may facilitate and support diagnostics in clinical practice. Objectives To create a reliable deep learning tool for the detection of active inflammatory and structural changes indicative of axSpA on MRI of sacroiliac joints. Methods In this study, MRIs of sacroiliac joints from 477 patients from four cohorts (GESPIC-AS, GESPIC-Crohn, GESPIC-Uveitis and OptiRef comprising 266 patients with and 211 without axSpA) were used to develop a deep learning framework (randomly divided into training, n=404, and validation, n=73, datasets). MRIs from the ASAS cohort (n=116) were used for independent testing (test dataset). Each examination in the training/validation dataset was evaluated for the presence of active inflammatory and structural changes indicative of SpA by six experienced, trained and calibrated readers and by seven expert readers in the test dataset. The presence of the changes was defined as the majority vote amongst readers. Discordant cases in the training/validation dataset underwent consensus reading. In addition, the test dataset was evaluated by three radiologists not specifically trained in SpA. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity. Results The prevalence of positive imaging findings for active inflammatory/structural changes indicative of axSpA was 41%/51% in the training/validation dataset and 22%/22% in the test dataset. The model for the detection of active inflammatory changes showed an AUC of 0.91 (0.83 – 0.97) – Figure 1 – and an accuracy of 84% on the validation dataset; the corresponding sensitivity and specificity were 96% and 76%, respectively. Despite a substantially lower prevalence of active inflammatory changes in the test dataset, the model showed good generalization with an AUC of 0.91 (0.84−0.97) and an accuracy of 75%; the sensitivity and specificity were 88% and 71%, respectively. The model demonstrated a similar performance on the validation and test datasets for the detection of active inflammatory changes fulfilling the ASAS definition. The model for the detection of structural changes indicative of axSpA showed good performance on the validation dataset with an AUC of 0.90 (0.82-0.96) for the detection of structural changes and an overall accuracy of 85%. The associated sensitivity and specificity were 95% and 75%, respectively. The model showed reasonable generalization to new data with an AUC of 0.89 (0.81−0.96) and an accuracy of 79%; the sensitivity and specificity were 85% and 78%, respectively. Overall, the model performed close to the individual human experts - Figure 1. Conclusion The developed framework allowed the detection of active inflammatory and structural changes indicative of axSpA on MRI. This approach may be used as an assistant tool in the diagnostic workflow. Acknowledgements GESPIC-AS has been financially supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung - BMBF). GESPIC-Crohn has been supported by the Clinical Research Unit grant from the Berlin Institute of Health (BIH). GESPIC-Uveitis has been supported by a research grant from AbbVie. OptiRef has been supported by a research grant from Novartis. The Assessment of Spondyloarthritis International Society (ASAS) has supported the project with a research grant and provided access to the MRI images of the ASAS calssifiaction cohort. We want to thank colleagues who performed annotation of the images from the ASAS classification cohort: Pedro Machado, Mikkel Ostergaard, Suzanne Juhl Pedersen, Ulrich Weber. Further, we thank Torsten Karge for the development of the MRI reading interface for GESPIC and OptiRef images, Joel Paschke for development of the scoring interface for ASAS images. LCA is grateful for her participation in the BIH Charité–Junior Clinician and Clinician Scientist Program and KKB is grateful for his participation in the BIH Charité Digital Clinician Scientist Program all funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. JR is grateful for her participation in the BIH Charité–Junior Clinician and Clinician Scientist Program. Disclosure of Interests None declared

Abstract: According to international recommendations, the Ankylosing Spondylitis Disease Activity Score (ASDAS) is the preferred score for assessing disease activity in axial spondyloarthritis (axSpA) [1]. However, routine determination of C-reactive protein (CRP) to calculate ASDAS values takes hours to days. This limits the use of ASDAS in clinical routine and clinical trials and hinders the implementation of treat-to-target approaches in axSpA. Whereas quick quantitative CRP (qCRP) tests allow CRP assessment within a few minutes. In a pilot project the performance of qCRP-based ASDAS assessment (ASDAS-qCRP) was already investigated in a single center study of 50 newly diagnosed, bDMARD-naïve axSpA patients with promising results [2] . Objectives: To validate the ASDAS-qCRP in a prospective, multicenter study of axSpA patients in a typical axSpA cohort with an appropriate sample size. Methods: The study was conducted in five centers in Germany. Consecutive adult (≥ 18 years) axSpA patients were included. In addition to a rheumatological assessment, including patient reported outcomes (PROs), routine CRP and erythrocyte sedimentation rate (ESR) were measured in the local labs. Additionally, a qCRP testing with the „QuikRead go instrument“ (Aidian Oy, Finland) was performed at the study center (measurement range 0.5 - 200 mg/l for hematocrit concentrations of 40 – 45%). Statistical analysis included descriptive statistics, cross tabulation and weighted Cohen´s kappa comparing disease activity categories, Bland-Altman plots and intraclass correlation coefficient (ICC) for ASDAS-CRP and ASDAS-qCRP. Results: In this study 251 axSpA patients were included between January and September 2020 (mean age: 38.4 years; mean disease duration: 6.2 years, 159 patients (63.3%) were male, 211 (84.1%) HLA-B27 positive and 195 (77.7%) were classified as radiographic axSpA). 143 patients (57.0%) were treated with bDMARDs. CRP and qCRP showed mean values of 2.12 and 2.17 mg/l, respectively. With the ASDAS-qCRP, 242 patients (96.4%) were assigned to the same disease activity category as compared to the ASDAS based on the conventional lab CRP measurement (Table 1). Weighted Cohen´s kappa was 0.966 (95%CI: 0.943; 0.988). ICC for ASDAS-CRP- and ASDAS-qCRP-values was 0.997 (95%CI: 0.994; 0.999). The agreement of ASDAS-qCRP and ASDAS-CRP is shown in a Bland-Altman plot (Figure 1). Table 1. Disease activity categories by ASDAS-qCRP vs. ASDAS-CRP ASDAS-qCRP (n = 251) Inactive Disease ( 〈 1.3) Low Disease Activity (1.3 - 〈 2.1) High Disease Activity (2.1 - 3.5) Very high Disease Activity ( 〉 3.5) ASDAS-CRP Inactive Disease ( 〈 1.3) 56 (22.3%) 2 (0.8%) Low Disease Activity (1.3 - 〈 2.1) 62 (24.7%) 7 (2.8%) High Disease Activity (2.1 - 3.5) 97 (38.6%) Very high Disease Activity ( 〉 3.5) 27 (10.8%) The fields highlighted in red indicate that disease activity categories do not match. ASDAS = Ankylosing Spondylitis Disease Activity Score, CRP = C-reactive protein, qCRP = quick quantitative CRP Conclusion: The ASDAS-qCRP and ASDAS-CRP showed an almost perfect agreement on the assignment to disease activity categories (96%) with the important advantage of time. With ASDAS-qCRP, rheumatologists could base their clinical decision-making on a disease activity measurement by using a composite score immediately. ASDAS-qCRP, therefore, can be integrated in clinical routine and clinical trials in the future and may facilitate implementation of the treat-to-target concept in axial SpA. References: [1]Smolen JS, et al. Ann Rheum Dis. 2018 Jan; 77(1):3-17. [2]Proft F, et al. Joint Bone Spine. 2019 Jul 29. Figure 1. Bland-Altman plot for ASDAS-qCRP and ASDAS-CRP Acknowledgements: The authors would like to deeply thank Braun T, Doerwald C, Deter N, Höppner C, Lackinger J, Lorenz C, Lunkwitz K, Mandt B, Sron S and Zernicke J for their practical support and coordinating the study. Funding statement: The AQUA study was supported by an unrestricted research grant from Novartis. Testing kits were provided free of charge from Aidian Oy, Finland. Disclosure of Interests: None declared

Abstract: The aim of this study was to investigate the association between antiphospholipid antibodies and non-thrombotic and non-gestational manifestations of systemic lupus erythematosus. Methods Systemic lupus erythematosus patients with persistently positive antiphospholipid antibodies or lupus anticoagulant were identified and grouped as systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS), systemic lupus erythematosus with positive antiphospholipid antibodies/lupus anticoagulant without antiphospholipid syndrome (SLE-aPL), and systemic lupus erythematosus with negative aPLs (SLE-No aPL). Groups were compared in terms of non-thrombotic systemic lupus erythematosus manifestations and laboratory features retrospectively. Results A total of 150 systemic lupus erythematosus patients, 26 with SLE-APS, 25 with SLE-aPL, and 99 with SLE-No aPL, were identified. Livedo reticularis, neurologic involvement, and thrombocytopenia were more common in antiphospholipid antibody positive systemic lupus erythematosus cases. Malar rash, arthritis, and pleuritis were more common in the SLE-No aPL, SLE-APS, and SLE-aPL groups, respectively. Positivity rates and titers of specific antiphospholipid antibodies did not differ between the SLE-APS and SLE-aPL groups. Conclusions Presence of antiphospholipid syndrome or persistent antiphospholipid antibodies may be related to non-thrombotic and non-gestational systemic lupus erythematosus manifestations. Patients with systemic lupus erythematosus plus antiphospholipid syndrome and persistent antiphospholipid antibodies without antiphospholipid syndrome also differ in terms of systemic lupus erythematosus manifestations.