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Objective To analyse pro-survival mechanisms elicited in RA synovial fibroblasts (RASFs) upon detachment from their extracellular matrix dependent on the disintegrin metalloproteinase ADAM15 and Yes-associated protein kinase 1 (YAP1). Methods Detachment-induced apoptosis was determined by caspase 3/7 assays. Immunofluorescent stainings, cell surface biotinylation and immunoblotting were applied to analyse phosphorylated kinases and subcellular localization of YAP1 and connective tissue growth factor (CTGF). Caspase and transwell transmigration assays served to study CTGF function. Results Silencing of ADAM15 or YAP1 in RASFs leads to significantly increased levels of detachment-induced caspase activity. In non-silenced RASFs detachment causes simultaneous ADAM15-enhanced phosphorylation of YAP1 at S127, known for promoting its cytoplasmic localization, and Src-dependent phosphorylation at tyrosine Y357. The majority of nuclear YAP1 leaves the nucleus shortly after cell detachment, but prolonged detachment causes a marked nuclear re-entry of YAP1, resulting in significantly increased synthesis of CTGF. The newly synthesized CTGF, however, is not detectable in the supernatant, but is bound to the outside of the plasma membrane. In vitro studies demonstrated autocrine binding of CTGF to the EGF receptor and β1 integrin, with concomitant triggering of survival kinases, AKT1, ERK1/2, Src and focal adhesion kinase. Functional studies revealed anti-apoptotic effects of CTGF on detached RASFs and an enhancement of their potential for endothelial transmigration using HUVEC-coated transwells. Conclusion The elucidation of a new molecular mechanism that protects RASFs in the highly pro-apoptotic environment of inflamed RA joints by promoting anoikis-resistance and transendothelial migration via ADAM15/YAP1-mediated CTGF upregulation uncovers potentially new targets for future therapeutic intervention.

ObjectivesTo evaluate the ability of fluorescence-optical imaging (FOI) to detect preclinical musculoskeletal inflammatory signs in patients with skin psoriasis at risk of developing psoriatic arthritis (PsA).MethodsThis investigator-initiated prospective exploratory study evaluated adult patients with psoriasis with musculoskeletal complaints and/or nail psoriasis within the last 6 months. Patients underwent a comprehensive rheumatological clinical examination (CE) along with musculoskeletal ultrasound (MSUS) and FOI of both hands at a single visit. Patients with CE–/MSUS–/FOI+ findings had MRI performed on the symptomatic or dominant hand within 7 days. If MRI was negative, the patients were followed over 2 years for the onset of clinically manifest PsA.ResultsA total of 389 patients were referred from dermatology centres and evaluated at 14 rheumatology sites in Germany. Seventy-seven (20%) patients with CE−/US−/FOI− were considered to have psoriasis only. PsA was diagnosed in 140/389 patients (36%) based on CE alone and in another 55 patients (14%) by additional MSUS; overall, 50% of the patient cohort was diagnosed with PsA. One hundred sixteen patients (30%) were FOI+ (CE−) of which 40 (37%) were FOI+/MRI+. In the 2-year follow-up of the FOI+/CE− patients, clinical PsA was confirmed in another 12%.ConclusionFOI is a promising method for the detection of signs of musculoskeletal inflammation in hands that may serve as an early imaging biomarker for transitions from psoriasis to PsA. This imaging technique has the potential to detect PsA in at-risk patients with psoriasis, reduce time to PsA diagnosis and improve patient outcomes.

Objective To investigate the efficacy and safety of rituximab + LEF in patients with RA. Methods In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators’ control. Results Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders. Conclusion The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring. Trial registration EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958.

Objective The goal of this study was to evaluate the long-term impact of adalimumab therapy on work-related outcomes in employed patients with rheumatoid arthritis (RA). Method We utilized data from an observational cohort of German patients who initiated adalimumab treatment during routine clinical care. Analyses were based on employed patients (part-time or full-time) who continued adalimumab treatment for 24 months. Major outcomes were self-reported sick leave days in the previous 6 months, absenteeism, presenteeism, and total work productivity impairment as assessed by the Work Productivity and Activity Impairment (WPAI) questionnaire and disease activity assessments. The normal number of sick leave days was based on data from the German Federal Statistical Office. Results Of 783 patients, 72.3% were women, mean age was 47.9 years, and mean disease duration was 7.8 years. At baseline (before adalimumab initiation), 42.9% of patients had higher than normal sick leave days (> 5) in the previous 6 months. During 24 months of adalimumab treatment, 61% of patients with higher than normal sick leave days at baseline returned to normal sick leave values (≤ 5 days/6 months). Overall, mean sick leave days/6 months decreased from 14.8 days at baseline to 7.4 days at month 24. Improvements were observed in WPAI assessments and disease activity measures, although presenteeism levels remained high (32.2% at month 24). Conclusions Adalimumab treatment was associated with strong and sustained improvements in work-related outcomes in employed patients who continued on adalimumab for 24 months. Presenteeism appears to be the work outcome most resistant to improvement during RA treatment. Trial registration NCT01076205 Key Points• Long-term adalimumab therapy was associated with sustained improvements in work outcomes in patients with rheumatoid arthritis.• Despite improvements in sick leave days and work absenteeism, presenteeism (impairment while at work) remained relatively high.

Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-dcrit) in rheumatoid arthritis (RA) patients treated with intravenous tocilizumab or comparator anti-tumor necrosis factor (TNF) agents. The previously published DAS28-dcrit value [DAS28 decrease (improvement) ≥ 1.8] was retrospectively applied to data from two studies of tocilizumab in RA, the 52-week ACT-iON observational study and the 24-week ADACTA randomized study. Data were compared within (not between) studies. DAS28 was calculated with erythrocyte sedimentation rate as the inflammatory marker. Stability of DAS28-dcrit responses and European League Against Rheumatism (EULAR) good responses was determined by evaluating repeated responses at subsequent timepoints. A logistic regression model was used to calculate p values for differences in response rates between active agents. Patient-reported outcomes (PROs; pain, global health, function, and fatigue) in DAS28-dcrit responder versus non-responder groups were compared with an ANCOVA model. DAS28-dcrit individual response rates were 78.2% in tocilizumab-treated patients and 58.2% in anti-TNF-treated patients at week 52 in the ACT-ion study (p = 0.0001) and 90.1% versus 59.1% at week 24 in the ADACTA study (p crit responses showed greater stability over time (up to 52 weeks) than EULAR good responses. For both active treatments, DAS28-dcrit responses were associated with statistically significant improvements in mean PRO values compared with non-responders. The DAS28-dcrit response criterion provides robust assessments of individual responses to RA therapy and may be useful for discriminating between active agents in clinical studies and guiding treat-to-target decisions in daily practice.

Background: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. Methods: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. Results: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. Conclusions: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

ObjectivesRheumatoid arthritis (RA) is an autoimmune disease strongly associated with the major histocompatibility complex (MHC) class II allele DRB1*04:01, which encodes a protein that binds self-peptides for presentation to T cells. This study characterises the autoantigen-presenting function of DRB1*04:01 (HLA-DRA*01:01/HLA-DRB1*04:01) at a molecular level for prototypic T-cell determinants, focusing on a post-translationally modified collagen type II (Col2)-derived peptide.MethodsThe crystal structures of DRB1*04:01 molecules in complex with the peptides HSP70289-306, citrullinated CILP982-996and galactosylated Col2259-273were determined on cocrystallisation. T cells specific for Col2259-273were investigated in peripheral blood mononuclear cells from patients with DRB1*04:01-positive RA by cytofluorometric detection of the activation marker CD154 on peptide stimulation and binding of fluorescent DRB1*0401/Col2259-273tetramer complexes. The cDNAs encoding the T-cell receptor (TCR) α-chains and β-chains were cloned from single-cell sorted tetramer-positive T cells and transferred via a lentiviral vector into TCR-deficient Jurkat 76 cells.ResultsThe crystal structures identified peptide binding to DRB1*04:01 and potential side chain exposure to T cells. The main TCR recognition sites in Col2259-273were lysine residues that can be galactosylated. RA T-cell responses to DRB1*04:01-presented Col2259-273were dependent on peptide galactosylation at lysine 264. Dynamic molecular modelling of a functionally characterised Col2259-273-specific TCR complexed with DRB1*04:01/Col2259-273provided evidence for differential allosteric T-cell recognition of glycosylated lysine 264.ConclusionsThe MHC-peptide-TCR interactions elucidated in our study provide new molecular insights into recognition of a post-translationally modified RA T-cell determinant with a known dominant role in arthritogenic and tolerogenic responses in murine Col2-induced arthritis.

ObjectivesThe aim was to evaluate the safety and effectiveness of sarilumab in RA patients after inadequate response (IR) to janus kinase inhibitors (JAKi) and tocilizumab.MethodsThe prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites. RA patients were prospectively selected at the physician’s discretion according to label. This interim analysis included 536 patients over a treatment course of ≤6 months. Patients were stratified in four groups according to pretreatment before the start of sarilumab therapy: last prior treatment JAKi (JAKi-IR); last prior treatment tocilizumab (tocilizumab-IR); any other biological DMARD (bDMARD) in treatment history (bDMARD TH); and patients who had not received any bDMARDs or targeted synthetic (ts) DMARDs (b/tsDMARD naive) before.ResultsFor this preplanned interim analysis, 536 patients were included in the baseline population, of whom 502 patients had at least one corresponding post-baseline effectiveness assessment documented (main analysis population). In all analysed cohorts, safety was consistent with the anticipated profile of sarilumab, without new safety signals. Six months of sarilumab treatment attenuated disease activity in JAKi-IR, tocilizumab-IR, bDMARD TH and b/tsDMARD-naive patients to a very similar extent. Physical function did not change substantially over the course of treatment. Rates of premature study discontinuation were comparable between cohorts.ConclusionSarilumab treatment was effective in patients with IR to JAKi and tocilizumab, with an expectable safety profile and drug retention over 6 months. Confirmation of these promising results should encourage further studies on this treatment sequence, which is of high practical relevance.Study registrationPaul-Ehrlich-Institut—Federal Institute for Vaccine and Biomedics, SARILL08661.

Background The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functional status in rheumatoid arthritis (RA), but the change required for meaningful improvements remains unclear. A minimum clinically important difference (MCID) of 0.22 is frequently used in RA trials. The aim of this study was to determine a statistically defined critical difference for HAQ-DI (HAQ-DI-dcrit) and evaluate its association with therapeutic outcomes. Methods We retrospectively analyzed data from adult German patients with RA enrolled in a multicenter observational trial in which they received adalimumab therapy at the decision of the treating clinician during routine clinical care. The HAQ-DI-dcrit, defined as the minimum change that can be reliably discriminated from random long-term variations in patients on stable therapy, was determined by evaluating intra-individual variation in patient scores. Other outcomes of interest included Disease Activity Score-28 joints and patient-reported pain and fatigue. Results The HAQ-DI-dcrit was calculated as an improvement (decrease) from baseline of 0.68 in a discovery cohort (N = 1645) of RA patients on stable therapy and with moderate disease activity (mean DAS28 [standard deviation] of 4.4 [1.6]). In the full patient cohort (N = 2740), 22.1% of patients achieved a HAQ-DI-dcrit improvement at month 6. Compared with patients with a small improvement in HAQ-DI (decrease of ≥0.22 to crit at month 6 had better therapeutic outcomes at months 12 and 24, including stable functional improvements. Change in pain was the most important predictor of HAQ-DI improvement during the first 6 months of therapy. Conclusions A HAQ-DI-dcrit of 0.68 is a reliable measure of functional improvement. This measure may be useful in routine clinical care and clinical trials. Trial registration ClinicalTrials.gov NCT01076205. Registered on February 26, 2010 (retrospectively registered).

Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the “sneaking ligand” approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The prototype SLC1 binds specifically to the activated endothelium and blocks canonical NF-kappaB activation. In vivo, SLC1 attenuated clinical and histological signs of experimental arthritides. The SLFP architecture allows an easy exchange of binding and effector domains and represents an attractive approach to study disease-relevant biological targets in a broad range of diseases. In vivo, SLFP treatment might increase therapeutic efficacy while minimizing adverse effects.

Was ist neu? Bestehende Therapieempfehlungen und deren Limitationen In den letzten Jahren haben sich die Basistherapieoptionen für die Behandlung der Psoriasisarthritis deutlich erweitert. Das Sicherheitsprofil der verfügbaren Therapien ist gut untersucht und für die verschiedenen Präparate bekannt. Verschiedene Empfehlungen zur Auswahl und Steuerung der geeigneten Therapie stehen dem Behandler zur Verfügung. Hierbei finden die Empfehlungen der European League Against Rheumatism (EULAR) und der Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) national und international in der Routine Anwendung. Zugelassene Therapieoptionen zur Behandlung der Psoriasisarthritis csDMARD-Therapien haben im Vergleich zur RA in der PsA-Behandlung eine schlechte Evidenzlage. Für neue Substanzen in den Kategorien tsDMARD und bDMARD liegen höhere Evidenzniveaus vor. Da neue Therapien unterschiedliche Zielstrukturen adressieren, bieten sich zunehmend Chancen der personalisierten und individualisierten Therapieentscheidung. Gerade neue pathophysiologische Erkenntnisse zum Erkrankungsbild und die daraus resultierenden Therapieoptionen, die gezielt spezifische Targets adressieren, bieten Möglichkeiten einer immer differenzierteren und individualisierten medikamentösen Behandlung zur Verbesserung der Versorgung der PsA-Patienten, vor allem mit Fokus auf personalisierte Strategien zur optimalen Behandlung verschiedener Manifestationsformen und -muster. Randomisierte kontrollierte Studien und deren Relevanz für den Versorgungsalltag Studienendpunkte randomisierter kontrollierter Studien, deren Studiendesign oft aus der rheumatoiden Arthritis entliehen ist, dienen auch aufgrund der großen Heterogenität der Erkrankung kaum als Basis für individuelle Therapieentscheidungen. Ein mehrschrittiges Vorgehen bei der Auswahl eines individualisierten Behandlungsregimes ist wichtig unter Berücksichtigung der klinischen Manifestation, potenzieller Begleiterkrankungen, von Langzeitsicherheitsaspekten, Kontraindikationen, Applikationsformen und nicht zuletzt des Patientenwunschs.

Psoriatic arthritis is a heterogeneous immune-mediated disease that usually involves skin and joints but can also affect entheses and extraarticular structures in the disease course. In addition, associated diseases must be considered when choosing the appropriate therapeutic strategy. Different recommendations for treatment of psoriatic arthritis are available for clinical use. The recommendations of the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are the two internationally accepted guidelines frequently used to assist therapeutic decisions in clinical practice. New targeted treatment options developed based on a better knowledge of critical pathogenic pathways, will enlarge our armamentarium for optimized pharmacotherapy of psoriatic arthritis and improve personalized patient care.In den letzten Jahren haben sich die Basistherapieoptionen für die Behandlung der Psoriasisarthritis deutlich erweitert. Das Sicherheitsprofil der verfügbaren Therapien ist gut untersucht und für die verschiedenen Präparate bekannt. Verschiedene Empfehlungen zur Auswahl und Steuerung der geeigneten Therapie stehen dem Behandler zur Verfügung. Hierbei finden die Empfehlungen der European League Against Rheumatism (EULAR) und der Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) national und international in der Routine Anwendung. ZUGELASSENE THERAPIEOPTIONEN ZUR BEHANDLUNG DER PSORIASISARTHRITIS: csDMARD-Therapien haben im Vergleich zur RA in der PsA-Behandlung eine schlechte Evidenzlage. Für neue Substanzen in den Kategorien tsDMARD und bDMARD liegen höhere Evidenzniveaus vor. Da neue Therapien unterschiedliche Zielstrukturen adressieren, bieten sich zunehmend Chancen der personalisierten und individualisierten Therapieentscheidung. Gerade neue pathophysiologische Erkenntnisse zum Erkrankungsbild und die daraus resultierenden Therapieoptionen, die gezielt spezifische Targets adressieren, bieten Möglichkeiten einer immer differenzierteren und individualisierten medikamentösen Behandlung zur Verbesserung der Versorgung der PsA-Patienten, vor allem mit Fokus auf personalisierte Strategien zur optimalen Behandlung verschiedener Manifestationsformen und -muster. RANDOMISIERTE KONTROLLIERTE STUDIEN UND DEREN RELEVANZ FüR DEN VERSORGUNGSALLTAG: Studienendpunkte randomisierter kontrollierter Studien, deren Studiendesign oft aus der rheumatoiden Arthritis entliehen ist, dienen auch aufgrund der großen Heterogenität der Erkrankung kaum als Basis für individuelle Therapieentscheidungen. Ein mehrschrittiges Vorgehen bei der Auswahl eines individualisierten Behandlungsregimes ist wichtig unter Berücksichtigung der klinischen Manifestation, potenzieller Begleiterkrankungen, von Langzeitsicherheitsaspekten, Kontraindikationen, Applikationsformen und nicht zuletzt des Patientenwunschs.

Most studies of methotrexate (MTX) in combination with tumor necrosis factor (TNF) inhibitors have focused on treatment-naive patients with early disease. The goal of this study was to evaluate whether previous biologic therapy influenced the impact of concomitant MTX in patients initiating treatment with adalimumab. We retrospectively analyzed data from 2 large noninterventional studies of German patients with active rheumatoid arthritis (RA) who initiated adalimumab therapy during routine clinical practice. Patients were seen between April 2004 and February 2013 for study 1 and between April 2003 and March 2013 for study 2. Key outcomes were Disease Activity Score-28 joints (DAS28), patient global assessment of health (PGA), and pain. Subgroup analyses by prior biologic treatment were performed on patients treated with continuous adalimumab monotherapy or adalimumab plus MTX for 12 months and 2-sample t tests were used to evaluate differences. We also assessed outcomes in subgroups in which MTX had been added or removed at 6 months and compared outcomes with 1-sample t tests. Of 2654 patients, 1911 (72%) were biologic naive and 743 (28%) had received prior biologic therapy, usually with a TNF inhibitor. All subgroups showed improvements following initiation of adalimumab therapy. In patients with no previous biologic treatment, continuous adalimumab plus MTX was associated with greater improvements in DAS28, PGA, and pain at month 12 compared with continuous adalimumab monotherapy (P = .0006, .0031, and .0032, respectively). In patients with previous biologic treatment, concomitant MTX was associated with statistically significant benefits in pain only. Adding MTX at month 6 resulted in additional benefits in patients with no prior biologic therapy, but not those with previous biologics. We conclude that concomitant MTX resulted in additional improvements in DAS28 and PGA vs adalimumab monotherapy in patients with no previous biologic therapy, but changes were not statistically significant in patients treated with prior biologics. These findings may help inform the patient/provider treatment decision during routine clinical care.

Rheumatische Erkrankungen gehören zu den häufigsten chronisch entzündlichen Krankheiten. Neben ausgeprägter Schmerzhaftigkeit und progredienter Gelenkzerstörung reduzieren die rheumatoide Arthritis (RA), die Spondyloarthritiden (SpA) und die Psoriasisarthritis (PsA) die Arbeitsfähigkeit, die Lebensqualität und bei unzureichender Behandlung auch die Lebenserwartung. Seit der Einführung der Biologika zur Therapie dieser Erkrankungen hat die Suche nach geeigneten Biomarkern zur Frühdiagnostik und Vorhersage des Therapieerfolgs zunehmend an Bedeutung gewonnen. Das Hauptziel des Verbundes ArthroMark ist, neue Biomarker zu identifizieren und moderne Bildgebungsverfahren einzusetzen mit dem Ziel, die Diagnose, die Verlaufskontrolle und die Stratifizierung von Patienten mit RA, SpA und PsA zu verbessern. Mit der Entwicklung geeigneter Biomarker für diese Erkrankungen trägt dieses Vorhaben zur Gesundheitsforschung im Bereich chronischer Erkrankungen des Bewegungsapparates bei. Durch die Zusammenarbeit verschiedener nationaler Zentren sollen standortspezifische Ressourcen wie Probenbanken und klinische Studien gemeinsam nutzbar gemacht werden und individuelle Schwerpunkte in der Biomarkeranalyse mit einem entsprechenden Mehrwert vernetzt werden. Gemeinsames Datenmanagement und Vereinheitlichung der Datenerhebung sowie bestmögliche Charakterisierung der Patienten durch neue Bildgebungsmethoden sollen die Qualität der Markerprüfung optimieren.

Background:Although seronegative RA patients often present with substantial disease burden [1], patients are underrepresented in research cohorts or clinical trials. Consequently, less knowledge about this subgroup has been accumulated.Objectives:To describe outcome of seronegative vs. seropositive RA patients treated with sarilumab in regular care in Germany.Methods:The prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites, aiming to enroll up to 750 RA patients treated with sarilumab. RA patients are prospectively selected at physician’s discretion according to label, and medical history is documented before treatment. This interim analysis included patients with data available up to 24 months. Here we focus on sustained treatment response after 6 and 12 months, respectively. Patients were stratified according to serostatus (RF- AND ACPA- as seronegative or RF+ AND/OR ACPA+ as seropositive). All analyses are descriptive only.Results:To date 473 patients were included in the study, of which 22.2% (n=105) were seronegative and 59.0% (n=279) were seropositive (Table 1). For 89 patients (18.8%) serostatus was not specified.Table 1.Baseline data regarding patient characteristics, prior treatment and disease activityseronegativeseropositivepatients [n] (%)105(22.2)279(59.0)patient characteristicsSex female [n] (%)81(77.1)207(74.2)Age mean [years] (SD)56.6(12.5)59.6(10.9)BMI mean (SD) [kg/m2]29.2(6.7)28(6.0)Smoking history current/former [%]22.1/11.525.5/20.4Time since diagnosis of RA mean [years] (SD)7.9(7.6)11.5(9.9)prior RA treatmentcsDMARD [n] (%)102(97.1)273(97.8)bDMARD (TNFi) [n] (%)54(51.4)167(59.9)bDMARD (non-TNFi) [n] (%)32(30.5)83(29.7)tsDMARD (JAKi) [n] (%)25(23.8)57(20.4)disease activityCRP [mg/l] (SD)12.9(30.9)14.2(31.0)ESR [mm/h] (SD)23.7(20.5)25.3(22.4)SJC mean (SD)5.3(5.5)4.6(4.8)TJC mean (SD)10.2(8.2)7.2(6.6)HAQ-DI mean (SD)1.4(0.7)1.2(0.7)DAS28-ESR mean (SD)5.0(1.5)4.6(1.5)CDAI mean (SD)27.7(14.7)23.0(12.9)Fatigue [VAS] (SD)64.0(25.5)51.1(28.1)The mean time since diagnosis of RA was shorter in seronegative than in seropositive patients (7.9±7.6 years vs. 11.5±9.9 years) (Table 1).At baseline, CDAI score was 27.7±14.7 (n=104) and 23.0±12.9 (n=272) in seronegative and seropositive patients, respectively. After 12 months of sarilumab treatment, CDAI improved to 15.6±12.3 (n=38) and 9.1±8.7 (n=101) in seronegative and seropositive, respectively, for patients with post-baseline data available. At that time, remission/low disease activity according to CDAI was reached by 5.3% (n=2/38) / 39.5% (n=15/38) of seronegative patients, respectively and by 26.7% (n=27/101) / 68.3% (n=69/101) of seropositive patients, respectively (Fig. 1A, B).Figure 1.CDAI (A, B) and HAQ-DI (C) outcomes in seronegative and seropositive patientsPhysical function, assessed by HAQ-DI, was slightly more impaired in seronegative patients (1.4±0.7) than in seropositive patients (1.2±0.7) at baseline. HAQ-DI improved over 12 months to 0.9±0.7 in seropositive patients (n=90) but showed no change in seronegative patients (1.4±0.7; n=37) (Fig. 1C).Safety was consistent with the anticipated profile of IL-6-R-inhibition and no new safety signals occurred. Adverse events and serious adverse events were described in 61.7% and 12.8% of seronegative patients, respectively and in 55.2% and 13.7% of seropositive patients, respectively.Conclusion:Sarilumab treatment ameliorated CDAI in both seronegative (ΔCDAI -17.0±16.5) and seropositive (ΔCDAI -15.4±14.3) patients to the same extent over the course of 12 months, with a higher remission rate in seropositive patients. Functional capacity improved meaningfully in the seropositive cohort but had no significant impact in seronegative patients. The safety profile was consistent with data reported from controlled clinical trials.References:[1]Choi S-T et al. (2018) PLoS ONE 13(4): e0195550.Acknowledgements:We thank Cornelia Kühne (Haldensleben) for substantial contribution to patient recruitment in PROSARA.Disclosure of Interests:Harald Burkhardt Speakers bureau: Sanofi, Pfizer, Roche, Abb- vie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scribb, Janssen, and Novartis, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Grant/research support from: Pfizer, Roche, Abbvie, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Peer-Malte Aries Speakers bureau: Abbvie, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Consultant of: Abbvie, Celgene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Silke Zinke: None declared, Klaus Krueger Speakers bureau: Sanofi, Jonas Ahlers Employee of: Sanofi, Rolf Hecker Employee of: Sanofi, Inka Albrecht Employee of: Sanofi, Stefanie Kalus Consultant of: Sanofi, Oliver Bley Employee of: Sanofi, Patrizia Sternad: None declared, Ann-Dörthe Holst: None declared, Niklas Thomas Baerlecken: None declared, Thilo Klopsch: None declared, Martin Welcker Speakers bureau: Abbvie, Aescu, Amgen, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Consultant of: Abbvie, Actelion, Aescu, Amgen, Cel- gene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Grant/research support from: Abbvie, Novartis, UCB, Hexal, BMS, Lilly, Roche, Celgene, Sanofi, Eugen Feist Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi

Small molecules interfering with intracellular signalling pathways are used in the treatment of multiple diseases including RA. However, small molecules usually affect signalling in most cell types, not only in those which need to be targeted. This general inhibition of signalling pathways causes often adverse effects, which could be avoided by cell type-specific inhibitors. For cell-type specific modulation of signal transduction, we developed the sneaking ligand fusion proteins (SLFPs). SLFPs contain three domains: (1) the binding domain mediating cell type-specific targeting and endocytosis; (2) the endosomal release sequence releasing the effector domain into the cytoplasm; (3) the effector domain modulating signalling. Using our SLFP NF-kappaB inhibitor termed SLC1 we demonstrated that cell-type-specific modulation of intracellular signalling pathways is feasible, that endothelial NF-kappaB activation is critical for arthritis and peritonitis and that SLFPs help to identify disease-relevant pathways in defined cell types. Hence, SLFPs may improve risk-benefit ratios of therapeutic interventions.

The activation of intracellular signaling pathways such as the classical nuclear factor kappaB (NF-kappaB) pathway is related to the pathogenesis of several inflammatory autoimmune diseases including rheumatoid arthritis (RA). To clarify the role of disease-relevant cell-types and signaling molecules in vitro or in vivo, it is necessary to target them selectively without disturbing the homeostasis of the immune system. We developed sneaking ligand fusion proteins (SLFPs) for cell-type specific modulation of signaling pathways. We designed the first SLFPs to inhibit the activation of NF-kappaB, a key regulator of inflammation, solely in the activated endothelium. Our “sneaking ligand” NF-kappaB inhibitor (named SLC1) inhibits NF-kappaB activation specifically in E-selectin expressing cells in vitro and in mouse models of arthritis indicating the importance of NF-kappaB in the activated endothelium. Clinical signs of arthritis were ameliorated by SLC1 treatment. We conclude that the SLFP architecture consisting of easily exchangeable domains represents an attractive approach to utilize other disease-relevant biological targets both on the cell surface and intracellularly. By relying on two independent disease specific targets, SLFPs may increase the therapeutic efficacy and reduce adverse effects.

Hematological alterations can often be observed during rheumatic diseases. The effects can be clinically severe, ranging from anemia of different grades of severity, through increased risk of hemorrhage due to thrombocytopenia up to severe infections as a result of high-grade leukocytopenia. The clinical sequelae for patients are predominantly determined by the extent of cytopenia. The underlying disease itself can initially be considered as the cause. Examples are anemia as a result of chronic inflammation, antibody-mediated thrombocytopenia as in systemic lupus erythematosus (SLE) or granulocytopenia within the framework of Felty's syndrome. Immunosuppressive treatment also often leads to alterations in the blood constituents. Although some substances, such as cyclophosphamide can suppress all three cell types, there are also selective effects, such as isolated thrombocytopenia under treatment with tocilizumab and JAK inhibitors. The differential diagnostic clarification of cytopenia can be difficult and necessitates a systematic work-up of the course of the disease and the subsequent treatment. The reviews of anemia, leukocytopenia and thrombocytopenia presented here summarize the most important components of the differentiation of hematological alterations in patients with rheumatic diseases.

Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-d

Objective: Randomized trials have shown that concomitant methotrexate (MTX) augments the effectiveness of tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA), but its benefit in ps...

Background Spondylarthritidies (SpA) are characterized by different disease manifestations such as arthritis, enthesitis, dactylitis and associated to concomitant diseases like Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and crohn’s disease (CD). IBD might have a specific role to SpA due to common pathophysiological pathways. Characteristics of the rheumatic disease and response to treatment may differ within the phenotypic manifestation and with and without associated diseases. Adalimumab (ADA) is a monoclonal antibody inhibiting TNF alpha which has demonstrated efficacy in both, nraxSpA and ankylosing spondylitis (AS) as well as for UC and CD. Objectives To evaluate patient baseline characteristics prior to and treatment response on different disease manifestations in a cohort of AS patients with IBD compared to an AS without IBD during ADA treatment. Methods Data from a large German multicenter prospective observational non-interventional study (n=3.756) of patients with active AS who initiated ADA therapy during routine clinical care were analyzed with focus on specific patient groups: (1) patients with AS and IBD at baseline (n=166) and (2) patients with AS without IBD at baseline (n= 3.590). Patient characteristics and data of efficacy on different disease manifestations and prevalence of concomitant IBD over 24 months were analyzed. Results Of 3.756 patients in the main analysis set, 166 (4.4%) were identified to suffer from concomitant IBD at baseline. Baseline characteristics showed differences in gender distribution, proportion of patients with enthesitis, psoriasis and uveitis showing a higher proportion of each for the IBD group (Table). After 24 months of ADA treatment, both groups had similar decreases for BASDAI, BASMI, BASFI and dactylitis improvement. The IBD group had a fast decrease in BASDAI at M6 to its maximum improvement (delta of 1.9) which was kept stable until M24. For clearance of enthesitis, ADA had its largest therapeutic effect at M6 in the IBD group (clearance in 15.3% of the patients) while the AS without IBD group had the largest decrease of 10.2% at month 24. Resolving of uveitis with ADA therapy was more often seen in the IBD group compared to the AS without IBD (delta of 6% at M12 compared to delta of 2.6% at M12, respectively). The prevalence of IBD in AS in patients treated with ADA changed from 4.4% at baseline to 1.9% at M24. Conclusion Within the cohort of AS, patients’ characteristics of manifestations are associated to different treatment responses: Patients identified to have IBD at baseline respond better for resolving of enthesitis and show a faster response in BASDAI compared to the group without IBD. Overall a significant reduction in the prevalence of clinically relevant IBD was seen earliest at month 3 after ADA initiation. Acknowledgement This study was sponsored by AbbVie Deutschland GmbH & Co KG. AbbVie contributed to the study design, data analysis, and in the writing, revision, and approval of the abstract. Medical writing services were provided by CIRI, Frankfurt am Main, Germany, under contract with AbbVie for medical writing services. Disclosure of Interests Michaela Kohm Grant/research support from: BMS, Pfizer, Janssen, Consultant for: BMS, Pfizer, Janssen; AbbVie, Speakers bureau: BMS, Pfizer, Janssen, AbbVie, Marc Schmalzing Grant/research support from: Pfizer, Chugai, MSD, Janssen-Cilag, BMS, Celgene, UCB, Consultant for: Abbvie, Chugai, Genzyme, Hexal/Sandoz, MSD, Novartis, Roche, Sanofi Pasteur, Speakers bureau: Actelion, Baxalta/Shire, BMS, Celgene, Chugai, Janssen-Cilag, MSD, Novartis, Pfizer, Roche, UCB, Eva Christina Schwaneck: None declared, Holger Gnann: None declared, Hans-Peter Tony Consultant for: Eli Lilly and Company, Speakers bureau: Eli Lilly and Company, Gerd Greger : None declared, Annika Boas Shareholder of: AbbVie, Harald Burkhardt Grant/research support from: BMS, Pfizer, Janssen, Consultant for: AbbVie, BMS, Pfizer, Janssen, Roche, Chugai, Speakers bureau: AbbVie, BMS, Pfizer, Janssen, Roche, Chugai, Frank Behrens Grant/research support from: AbbVie, Pfizer, Roche, Chugai, Prophylix, Bioline, Novartis, Consultant for: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Eli Lilly, Speakers bureau: Ad board: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, Novartis, Biotest, Janssen, Genzyme, Eli Lilly

Background Rheumatoid Arthritis (RA) is a chronic inflammatory joint disease affecting approx. 1% of the adult population of Northern Europe. Strategies for its early detection and diagnosis are of high importance as prompt treatment improves clinical and structural outcome. Formation of autoantibodies against cyclic citrullinated proteins (anti-CCP) are identified to be associated to RA-development. Non-specific musculoskeletal (nsMSK) pain often precedes early RA-development. Often, patients with initial symptoms are referred to General Practitioners (GP) without access to a sensitive rheumatologic assessment. Objectives To evaluate incidence of patients with positivity in anti-CCP rapid-test and signs and symptoms of subclinical and clinical inflammation in a on risk-population for RA. Methods In this prospective study (PANORA), 980 patients with new onset of nsMSK pain at GP were included in 77 GP sites in Germany. In case of positivity in anti-CCP rapid-test (CCPoint®), patients were referred to Rheumatology Department (RD) for assessment and RA-evaluation. At RD, validation of anti-CCP testing (using ELISA) and a rheumatological examination including ultrasound was performed. Subclinical signs of inflammation defined as increase of microvascularisation were monitored by Fluorescence-optical imaging (FOI). In case of ELISA positivity but missing clinical evidence of RA, patients are monitored every 6 months for a total follow-up of 36 months or until RA-diagnosis. Results Data from 980 patients with completion of visits at GP and/or RD was analyzed from which 9.8% (n=94) of the patients showed a positive anti-CCP rapid-test at GP. At RD, 21% (n=25) of the rapid-test positive patients were confirmed anti-CCP-positive by ELISA. 10 patients were diagnosed with RA (1 in the ELISA negative group), thereof one case of a newly detected RA at month 6 of the follow-up period. In the three groups at baseline (figure 1), age was well balanced, the proportion of female patients was highest in the RA-diagnosis cohort (80%) as well as the proportion of patient with current or past smoking-status (40% vs. 22.2% in the RA-/ELISA- group). Conclusion Here, for the first time data from patients suspect for RA development (non-specific musculoskeletal pain within the last 6 months) and screened using anti-CCP point-of-care test at GP are reported. Within the group re-evaluated at RD due to positive point-of-care test, only 21% were confirmed positive using ELISA testing. In the screened population, already 10 patients were diagnosed as RA at RD including 1 patient in the follow-up period until now. The continuation of the PANORA patients in the follow-up period will give more insights in specific characteristics of the RA-risk population at early stages of the disease when combining serological and imaging markers using ultrasound and FOI. Disclosure of Interests Michaela Koehm Grant/research support from: BMS, Pfizer, Janssen, Consultant for: Pfizer, Celgene, Janssen, Speakers bureau: Pfizer, Celgene, Janssen, Ulf Henkemeier Grant/research support from: BMS, Tanja Rossmanith Grant/research support from: BMS, Pfizer, Janssen, Karola Mergenthal: None declared, Juliana J. Petersen: None declared, Harald Burkhardt Grant/research support from: BMS, Pfizer, Janssen, Consultant for: AbbVie, BMS, Pfizer, Janssen, Roche, Chugai, Speakers bureau: AbbVie, BMS, Pfizer, Janssen, Roche, Chugai, Frank Behrens Grant/research support from: AbbVie, Pfizer, Roche, Chugai, Prophylix, Bioline, Novartis, Consultant for: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Eli Lilly, Speakers bureau: Ad board: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, Novartis, Biotest, Janssen, Genzyme, Eli Lilly

Summary Introduction of biotherapeutics has been a major milestone in the treatment of different chronic diseases. Nevertheless, the immune system can recognize the administered biological as non-self and respond with generation of anti-drug antibodies (ADA), including neutralizing ADA (nADA). Immunogenic responses may result in altered drug dynamics and kinetics leading to changes in safety and efficacy. However, there are several challenges with standard techniques for immunogenicity testing. Ustekinumab (UST), used in different inflammatory diseases, is a therapeutic antibody directed against the shared p40 subunit of interleukin (IL)-12 and IL-23, interfering in the pathogenically crucial T helper type 1 (Th1)/Th17 pathway. We established and validated different approaches for detection and quantitation of UST, UST-specific ADA and nADA. Addressing the obstacle of complex formation of UST with nADA, we developed an acidification assay to approach the total amount of nADA. Validated methods were based on surface plasmon resonance spectroscopy (SPR), enzyme-linked immunosorbent assay (ELISA) and a cell-based approach to characterize neutralizing capacity of nADA. Parameters assessed were determination and quantitation limits, linearity, range, precision, accuracy and selectivity. Quantitation of ADA and UST was feasible at lower concentrations using ELISA, whereas SPR showed a wider linear range for determination of ADA and UST. Accuracy, precision and linearity for quantitation were comparable using ELISA, SPR and the cell-based approach. All validated parameters fulfill the requirements of regulatory agencies. A combination of the testing approaches could address the increasing demand of precision medicine as it can be suitable for capturing the whole spectrum of immunogenicity and is transferable to other biologicals.

Objective To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Asberg Depression Rating Scale (MADRS), a standardized structured interview. Methods In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test–retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. Results According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ 80%) when using the MADRS as the gold standard. Conclusion The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity.

Objective To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis. Methods We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (dcrit) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort). Results In the discovery cohort (n = 700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n = 2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-dcrit (>1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-dcrit response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-dcrit response at month 12, and 59.1% did not achieve any significant PRO responses. Conclusion The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management.

Objective. ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. Methods. We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. Results. Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease. Conclusion. As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity. Trial registration: ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01111240","term_id":"NCT01111240"}}NCT01111240

Background:Psoriasis (Pso) is one of the most common chronic inflammatory skin diseases in Europe. Psoriatic arthritis (PsA) is closely associated to Pso whereas the skin manifestation appears usually years before PsA-related symptoms emerge. Up to 30% of Pso patients develop PsA, but there is no clear correlation between disease duration of Pso and PsA development. Therefore, biomarkers for its early detection are of major importance. In early PsA, changes in synovial vascularisation combined with increased expression of proangiogenic factors appear first. Therefore, imaging biomarkers for detection of changes in vascularisation might be useful for early detection of musculoskeletal disease. Fluorescence-optical imaging (FOI) is a new method to detect changes in microvascularisation of the hands.Objectives:To determine the number of positive PsA diagnosis within a 24 month follow-up period in PsO only patients with subclinical MSK-inflammation detected in FOI.Methods:Sensitivity of FOI for detection of subclinical signs of musculoskeletal inflammation as biomarker for early PsA was observed in a prospective, multicentre study (XCITING) including patients with dermatological confirmed skin psoriasis. 411 patients were included from dermatology care units across Germany without diagnosis of PsA but potential risk factors for its development (nail psoriasis and/or joint pain or swelling within the last 6 months). Clinical examination (CE; swollen (66) and tender (68) joint count, enthesitis, dactylitis assessment) and standardised ultrasound (US) assessment was performed by a qualified rheumatologist to assess musculoskeletal inflammation. FOI was performed additionally. Data was analysed in focus on increased vascularisation of musculoskeletal structures as inflammatory markers. In case of discrepant results (positive FOI and negative CE and US), MRI was performed to prove the findings. In case of MRI negativity, a follow-up period of 24-months was performed including FOI, CE, US and MRI assessment.Results:83 of the 411 patients of the cohort were negative in all assessments (Pso only), 136 of the 411 patients were classified as PsA by rheumatologic assessments. 119 patients showed subclinical signs of musculoskeletal inflammation in the central reading of FOI, whereas CE and US were negative. In 37,5% of those patients, subclinical inflammation was confirmed by MRI assessment. 22 patients of the cohort without MRI positivity were willing to be followed up until month 24. 5 (7.5%) patients developed a clinical PsA until month 24 whereas 7 (10.5%) patients converted to be FOI negative. In 5 patients an additional MRI examination was performed in which one patient showed positive signs for inflammation.Conclusion:FOI is an innovative method for measurement of changes in microvascularisation in the hands. 6/22 patients initial only positive in FOI (no clinical signs for PsA, negative US, negative MRI) developed either clinical evident PsA (n=5) or new inflammation in MRI (n=1) during follow-up of 24 months. Therefore, FOI positive signals in PsO patients increase the probability for PsA development.Figure 1.Flow Chart of the Follow-up period of the XCITING study.Disclosure of Interests:Michaela Köhm Grant/research support from: Pfizer, Janssen, BMS, LEO, Consultant of: BMS, Pfizer, Speakers bureau: Pfizer, BMS, Janssen, Novartis, Sarah Ohrndorf: None declared, Tanja Rossmanith Grant/research support from: Janssen, BMS, LEO, Pfizer, Marina Backhaus Grant/research support from: Pfizer, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Siegfried Wassenberg: None declared, Benjamin Köhler Grant/research support from: Pfizer, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai

Background:Psoriasis (Pso) is one of the most common chronic inflammatory skin diseases in Europe. Psoriatic arthritis (PsA) is closely associated to Pso whereas the skin manifestation appears usually years before PsA-related symptoms emerge. Up to 30% of Pso patients develop PsA, but there is no clear correlation between disease duration of Pso and PsA development. In early PsA, changes in synovial vascularisation combined with increased expression of proangiogenic factors appear first. Therefore, imaging biomarkers for detection of changes in vascularisation might be useful for early detection of musculoskeletal disease. Fluorescence-optical imaging (FOI) is an indocyanine green (ICG) tailored method to detect microvascular changes in the hands using ICG kinetics over 360 sec. Different methods for assessment of FOI are available. It has not yet been demonstrated to what extent these methods can be used to differentiate psoriasis from psoriasis arthritis.Objectives:To evaluate different reader dependent assessment methods to evaluate FOI in psoriasis and psoriatic arthritis.Methods:FOI data (clinical PsA n=137, PsO without PsA n=202) from an observational prospective multicentre trial in Germany was used for manual assessment of the films using two different published assessment methods:(1) FOI activity score (FOIAS) and (2) individual characteristics of ICG kinetics. For (1) FOIAS, the levels of signal enhancement were scored using a scoring system from 0 to 3 (0=no enhancement, 3=strong enhancement) per joint as well as an assessment of the summation picture. (2) Kinetics were determined by joint-related signal enhancements as well as by ICG related flow-on and flow-off behaviour. Time to the first appearance of the signal, the time to the maximum enhancement and the time to the end of the signal were determined.Results:By use of (1) FOIAS, the maximum score (overall signals of all joints assessed by FOIAS) showed a significant difference (p=0.0075) between PsA (mean 4.76) and PsO (mean 3.84). (2) Time to global maximum showed no significant difference (PsA mean 91.1 sec vs PsO 92.6 sec). Moreover, the mean time to maximum and clearance of ICG did not differ between the two diseases. The duration of the 3 phases of kinetic (phase 1: flow-in, phase 2: stable, phase 3: clearance) was 52.4 sec, 180.2 sec and 119.8 sec for PsA and 57.6 sec, 186.0 sec and 130.5 sec for PsO with an earlier phase 2 and 3 for PsA by trend. The most frequently affected joints in PsA (affected > 10%): PIP 3 right and PIP 5 right.Conclusion:FOI is a sensitive method to detect changes in microvascularisation in the hands. The use of the manual FOIAS is able to differentiate significantly between PsA and PsO patients by comparison of the sum of scores over all joints (maximum score). The assessment of ICG kinetics is limited to discriminate between musculoskeletal and joint disease, differentiation of diseases is only seen by trend. Both methods characterize disease states differently. A combination of both methods might be useful to increase the potential of manual assessment of FOI signals.Figure 1.Maximum sum score of FOIAS in PsO and PsA patients (p=0.0075 in two-sided t-test).Disclosure of Interests:Luis Haan: None declared, Ulf Henkemeier: None declared, Ann Christina Foldenauer: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, Michaela Köhm Grant/research support from: Pfizer, Janssen, BMS, LEO, Consultant of: BMS, Pfizer, Speakers bureau: Pfizer, BMS, Janssen, Novartis

Background:Rheumatoid Arthritis (RA) is a chronic inflammatory joint disease. Strategies for its early detection and diagnosis are of high importance as prompt treatment improves clinical and structural outcome. Autoantibodies against cyclic citrullinated proteins (anti-CCP) have been associated with RA-development. Non-specific musculoskeletal (nsMSK) symptoms are often described prior to RA development. Majority of patients with nsMSK symptoms present to their general practice (GP) first. Studies of early arthritis cohorts have shown that many early arthritis patients cannot be accurately diagnosed at their first visit and are often referred as undifferentiated arthritis patients.Objectives:To evaluate the incidence of anti-CCP positivity in patients with new onset of nsMSK symptoms and the incidence of RA in these patients over a 3-year follow-up period compared to anti-CPP negative patients.Methods:In this prospective study (PANORA), 978 patients with new onset of nsMSK symptoms were included in 77 GP sites in Germany. Patients with a positive anti-CCP rapid-test (CCPoint®) were referred to Rheumatology Department (RD) for rheumatological assessment, RA-evaluation and an anti-CCP validation test (ELISA). ELISA anti-CCP positive patients without RA were monitored every 6 months for a total follow-up of 36 months or until RA-diagnosis. Patients with a negative anti-CPP result (CCPoint® or ELISA) are followed up with a questionnaire after 1 and 3 y.Results:From 978 included patients, 105 (10.7%) were CCPoint® positive. 96 were tested with ELISA and 27 (28.1%) were confirmed anti-CCP positive. 9 (33.3%) were diagnosed with RA at the first RD visit (study visit 2); 4 further patients were diagnosed with RA during the follow-up (FU) period so far. Overall, 48.1% of ELISA-positive (ELISA+) patients were diagnosed with RA up to now; 11 ELISA+ patients are still in the FU period of the study. Of the 868 CCPoint® negative patients, currently, 282 have filled out a 1-year FU questionnaire; 3.5% of those reported a RA diagnosis (Table 1). As expected, clinical parameters at V2 (e.g. CRP, swollen and tender joint count) were worse in the ELISA+/RA+ group compared to the ELISA-/RA- group, but no obvious differences were detected between ELISA+ patients who were diagnosed with RA during the FU period (after V2) and ELISA-/RA- patientsTable 1.Number and percentage of patients with a RA diagnosisAnti-CCP statusVisit 2Follow-up*TotalPoint-of-Care Test --3.5% (10 of 282)#3.5% (10 of 282)#Point-of-Care Test + / ELISA -2.9% (2 of 69)0% (0 of 34)#2.9% (2 of 69)Point-of-Care Test + / ELISA +33.3% (9 of 27)14.8% (4 of 27)48.1% (13 of 27)$* 1 year-questionnaire for Point-of-Care Test and ELISA negative patients or every 6 months follow-up for ELISA positive patients;#Patient-reported;$11 patients are still in the follow-up phase of the studyConclusion:Currently, 48.1% of anti-CCP+ (ELISA) patients have received a RA diagnosis, whereas 3.5% of the anti-CCP- (CCPoint®) received a RA diagnosis (patient reported), which underlines, that anti-CCP can be used as a marker to identify high-risk patients in GP setting. While clinical parameters are correlated with the diagnosis of RA, they are not suited for predicting future RA development alone. Anti-CCP, possibly in combination with additional parameters imaging, might increase the likelihood to early diagnose or predict RA development.Figure 1.Study overview: Patient distribution depending on anti-CCP results and RA diagnosis.Disclosure of Interests:Stephanie Dauth Grant/research support from: BMS, Michaela Köhm Grant/research support from: Pfizer, Janssen, BMS, LEO, Consultant of: BMS, Pfizer, Speakers bureau: Pfizer, BMS, Janssen, Novartis, Timm Oberwahrenbrock Grant/research support from: BMS, Ulf Henkemeier: None declared, Tanja Rossmanith Grant/research support from: Janssen, BMS, LEO, Pfizer, Karola Mergenthal Grant/research support from: BMS, Juliana J. Petersen Grant/research support from: BMS, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai

Background:Deficient cellular degradation pathways such as autophagy and the ubiquitin proteasome system (UPS) show a correlation with the onset of neurodegenerative diseases. Especially immune-mediated inflammatory myopathies often show therapy-resistant phenotypes with medical need for further understanding of pathogenesis und possible treatment.Objectives:The aim of this work was to study an association of these two degradation pathways in a large group of different muscle entities and to examine a possible influence in the pathogenesis of the investigated muscle diseases. Furthermore, a potential benefit in diagnostics was studied using factors such as ubiquitin, p62, NBR1 and LC3 and their role as adapter molecules.Methods:We examined ubiquitin, p62, NBR1 and LC3 on muscle biopsies from patients with the diagnosis of s-IBM, dermato- and polymyositis, muscular dystrophy, neurogenic atrophy, myotonic dystrophy type II (PROMM) and metabolic myopathies such as Pompe and McArdle disease. Immunohistochemical single and double stainings as well as immunofluorescence stainings were performed on cryosections. Furthermore, Western blot analysis was performed. The use of a histological score, defined as the product of the frequency of positive fibres and staining intensity, was used to investigate possible differences between the diseases in the expression of the investigated factors.Results:Especially in s-IBM, myofibrillar myopathies and Pompe disease, proteasomal and autophagic markers were detected. On the other hand, neurogenic atrophy, McArdle disease and the majority of the myotonic dystrophies type II showed no positive signals, except for p62, which was detected especially in internalized nuclei and regenerative fibres. Overall, in all entities in regenerative and necrotic as well as in atrophic fibres, a positive staining for ubiquitin, p62, NBR1 and LC3 could be shown. Dermatomyositis showed a moderate immunoreactivity for p62 and NBR1 in the area of the perifascicular atrophy. Polymyositis showed a strong endomysial reaction in the area of the attacked muscle fibres, especially in the area of the lymphocytic infiltrates. The histological score showed that ubiquitin was significantly higher in s-IBM than in polymyositis. NBR1 was significantly higher in s-IBM than in dermatomyositis and muscular dystrophies. LC3 and p62 showed a significantly higher level in s-IBM as compared to dermatomyositis and polymyositis. Except for NBR1, a positive correlation of autophagic and proteasomal markers was shown in dermatomyositis. There was also a positive correlation between LC3 and ubiquitin in polymyositis. Using multivariate analysis and recursive partitioning, we could show a predictability of the diagnosis of s-IBM with a LC3 score above 3. On the other hand, a value below 3 excluded the diagnosis of s-IBM.Conclusion:In particular, s-IBM, myofibrillar myopathies and Pompe disease showed a possible involvement disturbed proteasomal and autophagic degradation pathways in their pathogenesis. In addition, p62 and NBR1 seemed to have an important role in the immune response. Furthermore, the altered autophagic and proteasomal degradation pathways may be involved in ageing processes, sarcopenia and disease. In particular, LC3 seems to be suitable as a screening marker to recognize an idiopathic inflammatory myopathy. The other markers, such as p62, LC3, and NBR1, would be able to distinguish between the subgroups of idiopathic inflammatory myopathies. Therefore, LC3 could be included as a marker in the routine of neuropathological diagnostics. Further studies are needed to fully understand the role of proteasomal and autophagic factors in possible immune suppressive and immune modulatory therapies and to assess possible side effects.Disclosure of Interests:Ulrich Drott: None declared, Patrick Harter: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Michel Mittelbronn: None declared

Background:Blockade of IL-6 signaling by sarilumab has been demonstrated to be an effective treatment approach for rheumatoid arthritis. Due to strict inclusion and exclusion criteria, randomized controlled trials may not represent the heterogeneous RA patient population encountered in regular care.Objectives:The current study investigated the safety and effectiveness of sarilumab in the treatment of RA in regular care in Germany.Methods:The prospective, observational, single-arm 24-months PROSARA study (SARILL08661) is currently running in Germany at 79 sites, aiming to include up to 750 RA patients treated with sarilumab. RA patients are selected at physician discretion and treated according to the label. Study objectives include the documentation of safety and various effectiveness outcomes. This interim analysis included patients with data available up to 12 weeks. All analyses are descriptive only.Results:To date 348 patients were included in the study; of which 265 patients had post-baseline data. The mean age of the patients analyzed was 58.6 years (24-83); 76.3% are female. The mean disease duration was 10.3 years; comorbidities were present in 80.7% of patients. At baseline, 32.5% were biologic naïve. Most common pretreatment with b/ts DMARDs included TNF-inhibitors (TNFi, 56.2%), non-TNFi biologics (29.1%) or JAK-inhibitors (JAKi, 17.4%). At baseline, 49% received sarilumab as monotherapy and 29% in combination with conventional DMARDs (not specified for 22%). After 12 weeks of treatment with sarilumab, the mean DAS28-ESR decreased from 5.0±1.46 to 3.0±1.44 and CDAI from 26.7±13.79 to 13.6±11.4, respectively. DAS28-ESR remission/ low disease activity was achieved in 42.8% [n=77/180 patients with valid data on this parameter]/ 59.4% [n=107/180] of patients; 13.6% [n=28/206] and 49% [n=101/206] of patients reached CDAI remission and low disease activity. Boolean remission was observed in 9.5% [n=19/201] of patients at week 12. HAQ-DI improved from 1.3 at baseline to 1.1 at week 12 (n=195). The mean CDAI improvement was similar for autoantibody-positive (RF and/or ACPA; CDAI -12.5 at week 12) compared to -negative patients (CDAI -15.4 at week 12). Patients switching from JAKi to sarilumab (n=32), were more severely affected, had longer disease duration and received more prior treatments than patients switched from another compound. Of note, similar efficacy was observed among patients that switched from JAKi to sarilumab vs patients switched from other DMARDs; disease activity outcome measures including DAS28, CDAI, TJC, SJC and global assessments improved consistently (Figure 1).Safety was consistent with the anticipated profile of IL-6-R-inhibition and no new safety signals occurred. Adverse events and serious adverse events were described in 33.9% and 6.3% of patients, respectively.Conclusion:Sarilumab administered in regular care demonstrated rapid and clinically meaningful improvement in a general RA patient population including patients switching from JAKi. The safety profile was consistent with data reported from controlled clinical trials.Disclosure of Interests:Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Peer-Malte Aries Consultant of: Sanofi, Speakers bureau: Sanofi, Silke Zinke: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Inka Albrecht Employee of: Sanofi, Oliver Bley Employee of: Sanofi, Michael Obermeier: None declared, Patrizia Sternad: None declared, Martin Welcker Grant/research support from: Abbvie, Novartis, UCB, Hexal, BMS, Lilly, Roche, Celgene, Sanofi, Consultant of: Abbvie, Actelion, Aescu, Amgen, Celgene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Speakers bureau: Abbvie, Aescu, Amgen, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Cornelia Kühne Grant/research support from: Novartis, Amgen, Roche/Chugai, Pfizer, Celgene, AbbVie, Sanofi, Ann-Dörthe Holst: None declared, Niklas Thomas Baerlecken: None declared, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi

Summary: Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease. : Han et al. report that genetic depletion of IL-38 in mice delays the resolution of imiquimod-induced psoriasis by increasing the production of the inflammatory cytokine IL-17A by skin-infiltrating T cells. Depleting these T cells or the receptor that is targeted by IL-38 reduces psoriatic skin inflammation. Keywords: IL-38, IL1RAPL1, IL-17, γδ T cells, psoriasis, inflammation

Background Use of biologicals such as Rituximab (RTX) in Rheumatoid Arthritis (RA) is effective and often only licensed in combination with Methotrexate (MTX). In cases of contraindications to or intolerances, other cDMARDs are frequently used in routine care without data from RCTs. Patients with positive antiCCP-status were identified in previous studies to better respond to RTX in combination with MTX. Objectives Here we present for the first-time data of the impact of antiCCP status on ACR response in the combinational therapy of RTX and Leflunomide (LEF). Methods A total of 189 patients with active RA (DAS28 >3.2 and at least 3 SJC and 3 TJC) despite stable LEF treatment were screened for a 52 weeks double-blind placebo controlled multicenter RCT. Patients were randomised to receive either two times 1000 mg RTX i.v. or PLA, followed by a second course of RTX of either two times 500 or 1000 mg at week 24. The primary endpoint of the study was superiority of RTX in ACR20 and 50 responses during 24 weeks treatment period. Adult patients who had inadequate response to more than one antiTNF or failed more than three cDMARDs were excluded. Disease activity was measured at each visit and compared according to antiCCP status. For safety evaluation, frequency and severity of adverse events were documented. Results Of 189 screened patients 148 were randomised. The mean age was 56 years; the mean body weight 76 kg and 74% were female. The disease activity (DAS28) at baseline was 5.57 for RTX and 5.54 for PLA. 57.1% of the patients were antiCCP-positive for RTX compared to 59.6% for PLA. In the RTX group, antiCCP-positive patients‘ disease duration was 8.8 years compared to 5.6 years in the antiCCP-negative group), DAS28 was 5.73 vs. 5.32 and CRP levels were 11.1 mg/L vs. 5.3 mg/L. RTX demonstrated significant superiority compared to PLA at week 16 in both, ACR 20 and ACR 50 response. AntiCCP-positive patients showed a higher probability to respond to the RTX/LEF treatment than antiCCP-negative patients (figure 1). 43 serious adverse events were reported, 27 of them in the RTX treatment group during the placebo-controlled period. Conclusions Here we report data of the first RCT investigating the combination of RTX with LEF in RA. The treatment with RTX in combination with LEF demonstrated significant efficacy compared to PLA for ACR20 and 50 responses with highest response level at week 16. AntiCCP-positive patients showed a higher probability for treatment response compared to antiCCP-negative ones. The combination of RTX and LEF demonstrated a reasonable safety profile. Disclosure of Interest M. Kohm Grant/research support from: Janssen, Roche, Pfizer, Speakers bureau: Novartis, Janssen, Celgene, Pfizer, T. Rossmanith: None declared, R. Alten: None declared, M. Aringer: None declared, M. Backhaus: None declared, G. Burmester: None declared, E. Feist: None declared, E. Herrmann: None declared, H. Kellner: None declared, A. Lehn: None declared, U. Muller-Ladner: None declared, A. Rubbert-Roth: None declared, H.-P. Tony: None declared, S. Wassenberg: None declared, H. Burkhardt: None declared, F. Behrens: None declared