J S Smolen’s research while affiliated with Medical University of Vienna and other places

Objective To characterise the frequency and influence of tenosynovitis and tendon damage on pain and hand function using clinical examination and ultrasound (US) in hand osteoarthritis (HOA). Methods We included 86 patients with HOA and 23 age- and sex-matched control subjects. Extensor and flexor tendons of both hands were assessed by clinical examination and US for tenosynovitis, tendon damage. Conventional radiographs were acquired. Hand function was evaluated by the function subtest of the M-SACRAH questionnaire and the Moberg pick-up test. K-means cluster analyses was calculated to assess clusters based on radiographic features and sonographic tendon scores. Results Ultrasound identified the involvement of ≥ 1 tendon in 60/86 (69.8%) HOA patients compared with 2/23 (8.7%) subjects (p< 0.01) in the control group. In the HOA group, US detected tendon damage more often in flexor tendons compared with extensor tendons (2.1% 0.9%, p= 0.03), while tenosynovitis was observed more often in extensor tendons compared with flexor tendons (8% vs 0.6%, p< 0001). The sensitivity and specificity of clinical examination to detect tendon involvement was 81.4% and 34.6%, respectively on the patient level and 14.5% and 83.8% on the tendon level. The cluster analyses revealed one cluster with more radiographic features of HOA and more tendon damage while more tenosynovitis was found in cluster 2. M-SACRAH function did not correlate with tendon involvement on US. Conclusion This study revealed a high frequency of tendon involvement in HOA. Tendon involvement on US did not impact hand function or self-reported pain.

Background CT-P47 which is recombinant humanized monoclonal antibody was developed as a candidate to the reference tocilizumab. Objectives The purpose of this study was to compare the pharmacokinetics (PK), safety, and immunogenicity of CT-P47, EU-approved tocilizumab (EU-tocilizumab) and US-licensed tocilizumab (US-tocilizumab) up to 56 days after a single intravenous infusion of 8 mg/kg in healthy Japanese subjects. Methods 133 subjects aged 18 to 54 years were randomized into 1:1:1 to receive either CT-P47, EU-tocilizumab or US-tocilizumab. The primary PK endpoints included area under the serum concentration-time curve (AUC) from time zero to infinity (AUC0-inf), AUC from time zero to the last quantifiable concentration (AUC0-last), and maximum serum concentration (Cmax). Secondary endpoints were additional PK, safety, and immunogenicity. Results Of the 133 randomized subjects, 132 subjects received the study drug (CT-P47:45; EU-tocilizumab:43; US-tocilizumab:44). The 90% confidence intervals for the geometric least squares mean ratios of each of the primary PK parameters (AUC0-inf, AUC0-last, Cmax) were within the predefined equivalence margin of 80% to 125% (Table 1). Secondary PK variables and mean serum concentrations of tocilizumab were also comparable among all groups (Figure 1). Overall, 24 (53.3%), 24 (55.8%) and 24 (54.5%) subjects reported ≥1 treatment-emergent adverse event (TEAE) in the CT-P47, EU-tocilizumab and US-tocilizumab groups, respectively. Neutrophil count decreased was the most commonly reported TEAE overall (15 [33.3%], 13 [30.2%] and 12 [27.3%] subjects, respectively). No treatment-emergent serious adverse event was reported. Overall, 5 (11.1%), 1 (2.3%) and 2 (4.5%) subjects in the CT-P47, EU-tocilizumab and US-tocilizumab groups, respectively, had ≥1 post-treatment positive result for anti-drug antibodies (ADA) and 2 (4.4%), 0 and 1 (2.3%) subjects, respectively, had ≥1 positive result post-treatment for neutralizing antibody. Primary PK parameters were slightly lower in subjects with any type of ADA compared with ADA negative subjects, at post-dose. Conclusion CT-P47, EU-tocilizumab, and US-tocilizumab were bioequivalent as measured by primary PK endpoints and CT-P47 was determined to be safe and well tolerated in healthy subjects as compared with the comparators. • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Figure 1. Mean (± SD) Serum Concentrations of Intravenous Tocilizumab (PK Set) Abbreviations: EU-tocilizumab, European Union-approved tocilizumab; PK, pharmacokinetic; SD, standard deviation; US-tocilizumab, US-licensed tocilizumab. REFERENCES NIL Acknowledgements NIL Disclosure of Interests Miwa Haranaka: None declared, Takashi Eto: None declared, Takanori Tanaka: None declared, Rie Yazawa: None declared, Gerd R. Burmester Chugai, Fresenius, Sanofi., Celltrion, Fresenius, Sanofi., Edward Keystone AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, Samsung Bioepsis, Sung Hyun Kim Celltrion, Inc., YunJu Bae Celltrion, Inc., JeeHye Suh Celltrion, Inc., Yunah Kim Celltrion, Inc., JaeYong Lee Celltrion, Inc., Josef S. Smolen Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche.

Background In patients (pts) with rheumatoid arthritis (RA), high rheumatoid factor (RF) levels are a poor prognostic factor and associated with higher disease activity, risk of progression, and decreased response to monoclonal antibodies (mAbs) targeting tumour necrosis factor (TNF).1,2,3 Recent data suggest pts with RA and high RF levels have better clinical responses to TNF inhibitors (TNFis) without a fragment crystallisable (Fc) portion, such as certolizumab pegol (CZP), compared to TNFis with an Fc.4,5 However, in pts with RA and high RF levels who have had previous inadequate responses or intolerance to TNFis, data on response to CZP are limited. These pts have poorer responses to subsequent biologic or targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs).⁶ Objectives To assess impact of RF levels and previous therapies on CZP efficacy outcomes in pts with RA, in a post hoc analysis of the REALISTIC trial. Methods REALISTIC (NCT00717236) was double-blind and placebo-controlled to Week (Wk) 12.⁷ Pts with inadequately controlled RA were randomised 4:1 to receive either CZP (400 mg subcutaneous [sc] at Wks 0, 2 and 4, followed by 200 mg sc every 2 weeks) or placebo (PBO) for a 12-wk period, after which all pts received open-label CZP. We report the following outcomes to Wk 36: Disease Activity Score 28 C-reactive protein (DAS28-CRP) score, DAS28-CRP <2.6, Clinical Disease Activity Index (CDAI) score, and CDAI remission (CDAI ≤2.8). Results are stratified by baseline RF level (≤ quartile 3 [Q3] vs >Q3) and prior TNFi use; data are reported as observed case. Results Overall, 751 CZP-randomised pts (RF ≤Q3 [<180 kU/L]: n=560, RF >Q3 [≥180 kU/L]: n=191) and 179 PBO-randomised pts (RF ≤Q3: n=135, RF >Q3: n=44) were included. Baseline demographics were similar between pts with RF ≤Q3 and >Q3, including number of previous DMARDs (Table 1).At Wk 12, TNFi-naïve pts treated with CZP had lower DAS28-CRP scores than PBO-receiving pts regardless of RF levels (CZP, mean [SD]: RF ≤Q3: 3.9 [1.3], RF >Q3: 3.8 [1.3], PBO: RF ≤Q3: 4.9 [1.4], RF >Q3: 4.9 [1.2] PBO), indicating no effect of RF on response to CZP. Interestingly, in pts with prior TNFi use (TNFi-IR), larger differences between DAS28-CRP scores were seen in pts with RF >Q3 than RF ≤Q3 for PBO-randomized pts (RF ≤Q3 4.7 [1.4], RF >Q3, 5.7 [1.4]) compared with CZP (RF ≤Q3: 4.2 [1.4], RF >Q3: 4.2 [1.5]). Responses increased to Wk 36 in all CZP-randomised groups. At Wk 36, the proportion of CZP-randomised pts who achieved DAS28-CRP<2.6 was similar across RF levels and prior TNFi use (Figure 1). At Wk 12, TNFi-naïve CZP-randomised pts also had lower CDAI scores than PBO-randomised pts, regardless of RF levels (RF ≤Q3: 18.6 [13.9] CZP vs 27.3 [15.5] PBO; RF >Q3: 16.7 [12.1] CZP vs 26.9 [12.9] PBO). In TNFi-IR pts, larger differences between CDAI scores for CZP vs PBO were seen in pts with RF >Q3 compared with RF ≤Q3 (RF ≤Q3, mean [SD]: 21.6 [15.4] CZP vs 26.0 [15.8] PBO; RF >Q3, 20.4 [14.9] CZP vs 35.4 [18.2] PBO). Responses increased to Wk 36 in all CZP-randomised groups. The proportion of pts who achieved CDAI remission at Wk 36 was similar in CZP-randomised pts across RF levels and prior TNFi use (Figure 1). Conclusion In PBO-randomised TNF-IR pts responses were lower in the high RF group, compared with low RF (≤Q3). In contrast, pts with RA and high RF levels who were treated with CZP had similar clinical responses to those with low RF levels, indicating that RF does not influence the response to CZP. These data expand previous notions⁵ to a TNFi-IR population. Results may have treatment choice implications in pts with RA and high RF levels who have had inadequate responses to previous TNFi treatment. REFERENCES [1] Vastesaeger N. et al, Rheum 2009;48:1114–21. 2 Cuchacovich M. et al, Clin Rheumatol 2014;33(12):1707–14. 3 Takeuchi T. et al, Arthritis Res 2017;19:194. 4 Nakayama Y. Rheumatol Int 2022;42:1227–1234. 5 Smolen J. Arthritis Rheumatol 2023;75(suppl 9). 6 Pappas D.A. et al, Rheumatol Int 2021;41:585–593; 7 Weinblatt M.E. et al, Rheum 2012;51:2204–14. • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Acknowledgements Funded by UCB Pharma. Medical writing support provided by Costello Medical and funded by UCB Pharma. Disclosure of Interests Josef S. Smolen Honoraria from: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, Sanofi and UCB Pharma, Research grants from: Abbvie, AstraZeneca, Eli Lilly, Novartis and Roche, Ted Mikuls Consultant for: Horizon Therapeutics; Pfizer, Sanofi and UCB Pharma. Royalties from: Wolters Kluwer Health (UpToDate) and Elsevier., Research support from: Horizon Therapeutics, James Galloway Abbvie, Galapagos, Janssen, Eli Lilly, Pfizer and UCB Pharma, GSK, Pfizer, Ulf Müller-Ladner UCB Pharma, Jeffrey R Curtis Grant/research and consultancy fees: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma., Grant/research and consultancy fees from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma., Motomu Hashimoto Speaker fees from Bristol Myers, Chugai, Eisai, Eli Lilly, Tanabe and Mitsubishi., Research grants from Abbvie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, Eli Lilly, Novartis and Taisho Toyama., Tsutomu Takeuchi Received honoraria from AbbVie, Asahikasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Mitsubishi-Tanabe and Pfizer Japan., Received grants from AbbVie, Asahikasei, AYUMI, Chugai and Mitsubishi-Tanabe., Ernest Choy Speaker fees from Abbvie, Amgen, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly, Fresenius Kai, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, RPharm, Roche, Sanofi and UCB Pharma., Consultancy fees from Abbvie, Amgen, Biogen, Biocon, Chugai, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm and Sanofi., Research grants from Bio-Cancer, Biogen, Novartis, Pfizer and Sanofi., Yoshiya Tanaka Speaker fees and/or honoraria from: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Gilead, GLAXOSMITHKLINE, Pfizer, Taiho Pharmaceutical and Taisho, Received grants from: Chugai, Eisai, Mitsubishi-Tanabe and Taisho, Carlos Cara UCB Pharma, UCB Pharma, Bernard Lauwerys UCB Pharma, UCB Pharma, Nicola Tilt UCB Pharma, UCB Pharma, Baran Ufuktepe UCB Pharma, Peter C. Taylor Consultancy fees from: AbbVie, Eli Lilly, UCB Pharma, Pfizer, Biogen, Janssen, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Nordic Pharma, Acelyrin Inc. Participation on a Data Safety Monitoring Board/Advisory Board for Immunovant, Sanofi and Kymab., Galapagos.

Background CT-P47 is a recombinant humanized monoclonal antibody developed as a proposed biosimilar of tocilizumab. Pharmacokinetic (PK) equivalence between CT-P47 and reference tocilizumab was previously demonstrated in a phase I study (EULAR 2023, AB0402). Objectives The primary purpose of the current two studies was to compare PK similarity between CT-P47 auto-injector (AI) vs. pre-filled syringe (PFS) and to evaluate the usability of CT-P47 AI. Methods In PK study, 314 healthy subjects aged 19 to 55 years were randomized 1:1 to receive a single dose (162 mg) of CT-P47 AI or PFS. The primary objective was to demonstrate PK similarity in terms of AUC0-inf and Cmax.In usability study, 33 patients with moderate to severe rheumatoid arthritis (RA) aged 18 to 70 years received CT-P47 AI at Week 0 and 2, then by PFS every other week or weekly up to Week 10. The primary objective was usability of AI as assessed by patients‘ rating using POST-self-injection assessment questionnaire (SIAQ) at Week 2. The patients completed each item of SIAQ, which was transformed from 0 (worst experience) to 10 (best experience). Results In PK study, 310 subjects (153 in AI, 157 in PFS) initiated treatment. Baseline characteristics were similar between groups.The 90% CIs of the ratio of the geometric means for all primary PK endpoints (AUC0-inf and Cmax) were within the equivalence margin of 80% to 125%, indicating achievement of PK similarity between groups (Table 1). The secondary PK endpoints (AUC0-last, Tmax, t1/2, λz, CL/F, Vz/F, %AUCext) were also comparable between groups. Overall, 159 subjects experienced at least 1 Treatment-emergent adverse events (TEAE) with similar proportion (AI: 53.6%, PFS: 49.0%). Most of the TEAEs were grade 1 or 2 and related TEAEs were similar between groups (AI: 41.8%, PFS: 38.2%). There were no deaths, treatment-emergent serious adverse events (TESAE) and TEAEs leading to study drug discontinuation. Generally, TEAEs of special interest (TEAESIs) (Infection, Hypersensitivity, including anaphylaxis, Injection site reaction, Hepatic event and Hemorrhage [not medically significant bleeding]) were similar between groups and TEAESIs classified as gastrointestinal perforation, malignancy, or demyelinating disorder were not reported. The proportion of subjects who developed anti-drug antibody (ADA) (AI: 17.0%, PFS: 20.4%) and neutralizing antibody (NAb) (AI: 7.8%, PFS: 8.9%) at end of study (EOS) was comparable between groups. In the analysis of PK by ADA status, there was no distinct impact of ADA status on serum concentration. In usability study, the patients were generally confident about self-injection prior to the first injection, and high mean SIAQ scores were maintained post-injection and tended to be slightly higher than pre-injection (Table 2). All patients were able to successfully complete all instructions from checklist. In respect to efficacy, the mean scores for DAS28 (CRP and ESR) decreased from baseline up to Week 12. Overall, 22 TEAEs were reported in 36.4% patients. The majority of TEAEs were grade 1 or 2. The most common TEAEs regardless of relationship were leukopenia, neutropenia and injection site reaction (9.1% patients each). There was one TESAE and 6.1% patients experienced a TEAE leading to study drug discontinuation. The TEAESI of infection, injection site reaction and hepatic event, were reported for 12.1%, 9.1% and 3.0% patients, respectively. Hypersensitivity, hemorrhage, gastrointestinal perforation, malignancy, and demyelinating disorder were not reported. There was no device-related AE or death. Two patients had positive ADA result in post-treatment visits and were also positive for NAbs. Conclusion PK similarity of CT-P47 AI and PFS was demonstrated in healthy subjects and high usability of CT-P47 AI was observed in RA patients. Also, CT-P47 AI was well tolerated and no new safety signal was found in both studies. These results suggest that the CT-P47 administered via AI could be an alternative option for tocilizumab treatment to patients, caregivers and healthcare professionals. • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint REFERENCES: NIL. Acknowledgements NIL Disclosure of Interests Edward Keystone AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, Samsung Bioepsis, Gerd R. Burmester Chugai, Fresenius, Sanofi, Celltrion, Fresenius, Sanofi, Celltrion, Fresenius, Sanofi, Josef S. Smolen Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche, Kyung-Sang Yu: None declared, Hyunwook Ryu: None declared, Dongseong Shin: None declared, MinKyu Park: None declared, JunGi Hwang: None declared, Seol Ju Moon: None declared, MinGul Kim: None declared, Piotr Adrian Klimiuk: None declared, Jakub Trefler: None declared, Janusz Jaworski: None declared, Sung Hyun Kim Celltrion, Inc., YunJu Bae Celltrion, Inc., Dabee Jeon Celltrion, Inc., Hyunseung Lee Celltrion, Inc., Jiyoung Jang Celltrion, Inc., Jihun Bae Celltrion, Inc, hojae Lee Celltrion, Inc.

Background CT-P47 is a recombinant humanized monoclonal antibody developed as a proposed biosimilar of tocilizumab. Here we report the study results from a comparative clinical trial. Objectives The purpose of this study was to compare the efficacy and safety of CT-P47 with reference tocilizumab (ref-tocilizumab) in patients with active moderate-to-severe rheumatoid arthritis (RA). Methods Patients with moderate-to-severe RA who had inadequate response to ≥1 disease-modifying antirheumatic drugs were randomized 1:1 to receive 8 mg/kg of CT-P47 or ref-tocilizumab every 4 weeks up to Week 20. Prior to dosing at Week 24, patients in ref-tocilizumab group were re-randomized either to continue with ref-tocilizumab or undergo transition to CT-P47. Patients initially assigned to CT-P47 continued CT-P47 treatment until Week 48. The primary endpoint was mean change from baseline of disease activity score 28 (DAS28) (erythrocyte segmentation rate [ESR]) at two timepoints of Week 12 and Week 24 considering different regulatory requirement. Additional efficacy, PK and safety including immunogenicity were also evaluated. Results 471 randomized patients initiated treatment (CT-P47 in 234; ref-tocilizumab in 237). Baseline characteristics were similar between groups. The least squares mean (standard error) change from baseline of DAS28 (ESR) by analysis of covariate (ANCOVA) was -3.01 (0.121) and -3.00 (0.120) at Week 12 and by ANCOVA with multiple imputation was -3.77 (0.120) and -3.67 (0.118) at Week 24 for CT-P47 and ref-tocilizumab, respectively. The confidence intervals (CIs) of treatment difference were entirely within the predefined equivalence margins of Week 12: ±0.6 (95% CI: -0.01 [-0.26 to 0.24]) and Week 24: -0.6 to 0.5 (90% CI: -0.10 [-0.30 to 0.10]). Secondary efficacy endpoints up to Week 24 showed gradual improvement and were also similar between groups (Table 1) and maintained with slight improvement from Weeks 24 to 32.Mean serum concentration was similar between groups up to Week 32 (Week 24: CT-P47; 14.63 μg/mL vs ref-tocilizumab; 15.14 μg/mL). Up to Week 24 predose, 375 patients (CT-P47: 80.3% vs. ref-tocilizumab: 78.9%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common TEAE was upper respiratory tract infection (21.4%) in the CT-P47 and alanine aminotransferase increased (20.3%) in the ref-tocilizumab. Similar proportions of patients in both groups experienced at least 1 serious TEAE, TEAE classified as hypersensitivity reactions, hepatic event, and hemorrhage. From Weeks 24 to 32, the proportion of patients in overall TEAEs were also similar among groups (Table 2). Up to Week 32, the proportion of patients who had at least 1 anti-drug antibody positive result at post-treatment was similar between groups (CT-P47: 5.1% vs. ref-tocilizumab: 5.5%), and 4.7% in CT-P47 and 4.2% in ref-tocilizumab also had at least 1 neutralizing antibody positive result at post-treatment. Conclusion The results demonstrated that CT-P47 was equivalent to ref-tocilizumab as measured by the DAS28 (ESR). Also, efficacy, PK, safety and immunogenicity profiles were comparable among groups after Week 24 up to Week 32. Thus, this study supports the biosimilarity of CT-P47 to ref-tocilizumab and clinical evidence for switching from ref-tocilizumab to CT-P47.View this table: • View inline • View popup Table 1. Secondary Efficacy Results at Week 24 (ITT Set) • Download figure • Open in new tab • Download powerpoint REFERENCES: NIL. Acknowledgements NIL Disclosure of Interests Josef S. Smolen Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche, Jakub Trefler: None declared, Artur Racewicz: None declared, Janusz Jaworski: None declared, Agnieszka Zielinska: None declared, Marek Krogulec: None declared, Sławomir Jeka Abbvie, Amgen, Celgene, Lilly, Novartis, Roche, Sandoz, Sobi, UCB,, Rafał Wojciechowski Eli Lilly, Novartis, UCB, Janssen, Katarzyna Kolossa: None declared, Anna Dudek: None declared, Magdalena Krajewska-Włodarczyk: None declared, Paweł Hrycaj: None declared, Piotr Adrian Klimiuk: None declared, Gerd R. Burmester Chugai, Fresenius, Sanofi, Celltrion, Fresenius, Sanofi, Sung Hyun Kim Celltrion, Inc., YunJu Bae Celltrion, Inc., Dabee Jeon Celltrion, Inc., GoEun Yang Celltrion, Inc., YooBin Jung Celltrion, Inc., JiWoo Hong Celltrion, Inc., Edward Keystone AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, Samsung Bioepsis

Background Dendritic cells are innate immune cells known for their role in antigen presentation and activation of the adaptive immune system. However, their role in the pathogenesis of inflammatory arthritis is poorly defined. Objectives We aimed to elucidate the role of dendritic cells in models of inflammatory arthritis with special emphasis on inflammatory bone destruction. Methods CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OCs of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs. Results Targeting CD11c⁺ cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. We demonstrate that OCs are derived from CD11c⁺ cells and from Zbtb46⁺ conventional dendritic cells (cDCs) as all OCs in CD11c-Tomato and Zbtb46-Tomato fate reporter mice are Tomato⁺. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs. Conclusion Taken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, and targeting them might open new avenues for therapeutic interventions in OC-mediated diseases. • Download figure • Open in new tab • Download powerpoint Figure 1. Histological analysis of murine paws in a KBxN arthritis model of CD11cDTRtg mice. Mice injected with diphteria toxin (DT) displayed depletion of DCs. Shown is the quantitative analysis of inflammation, bone erosion area and number of synovial osteoclasts (OCs). REFERENCES NIL Acknowledgements NIL Disclosure of Interests Antonia Mazzucato-Puchner: None declared, Elisabeth Simader Lilly, Abbvie, Victoria Saferding Janssen, Melanie Hofmann: None declared, Markus Kieler: None declared, Rene Pfeifle: None declared, Gerhard Krönke: None declared, Josef S. Smolen speakers’ bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; participation on a data safety monitoring/advisory board for AstraZeneca., grants from AbbVie, Astra-Zeneca, Lilly and Galapagos;, Silvia Hayer: None declared, Günter Steiner reports about speakers’ bureau from Thermo Fisher Scientific, Daniel Aletaha reports about speakers’ bureau from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, and Sandoz, Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, and Sandoz, grants from Abbvie, Amgen, Galapagos, Lilly, and Sanofi;, Stephan Blüml: None declared.

Background Therapeutic advances of the recent past have led to significant changes in clinical practice when treating patients with rheumatoid arthritis (RA). Since the advent of biological disease modifying anti-rheumatic drugs (DMARD), double-blind randomized controlled trials (RCT) have been the mainstay of drug development. Over time, a significant increase in placebo response rates has been observed in these trials. We hypothesized that one element contributing to these increasing placebo responses are changing recruitment patterns with an increasing move towards geographic areas with less affluent health care systems. Objectives To determine the contribution of changes in geographic recruiting patterns to placebo response rates in RA. Methods We analysed the placebo arms of all available trials with reports on ACR response rates at week 12 and/or week 24. To ensure completeness of trial acquisition, we identified all placebo controlled RCTs investigating biological or targeted synthetic DMARDs in RA patients with established csDMARD background therapy through a systematic literature search covering the time from database inception until December 2nd, 2021. To assess geographic distribution, we extracted the numbers of recruiting centres per country from the original articles or from clinicaltrials.gov. We then used data published from the world bank on the per capita gross national product (GNP) of each recruiting country to calculate a weighted GNP per study, calculated as: weighted GNP=sum[(number of centres per country)*(GNP of respective country at study start)]/(total number of centres of that study). We performed linear mixed model regression with a random effect on study level (to control for study heterogeneity), weighted by the number of patients per study, and adjusted for the global trend of rising GNPs over time. Statistics were conducted using R (version 4.3.1). Results For complete trial evaluation, two independent researchers screened in total 12.793 articles, of which 522 were assessed in detail, with 122 articles finally fulfilling the criteria for trial analysis. Of the included studies the year of study start ranged from 1994 to 2019. All studies had low risk of bias using the version 2 of the Cochrane risk-of-bias tool for randomized trials. A significant positive association of placebo response rates with the study start year was found (estimate: 0.95; SE: 0.21; p<0.001). Recruitment areas have expanded from initially covering only North America and Western Europe to an increasing global recruitment over time (Figure 1), with more recent studies being conducted in less affluent countries. We identified a strong and significant negative association of the weighted and normalised GNP per study and placebo response rates in a study, with an estimate of -3.81% ACR20 response (SE 1.07; p<0.001; Figure 2) per 10.000 international Dollar. • Download figure • Open in new tab • Download powerpoint Figure 1. Patterns of recruiting centers (per country) from 1994 to 2019 (study start). • Download figure • Open in new tab • Download powerpoint Figure 2. Association of placebo response rates with the weighted gross national product (GNP) per study. The size of the bubbles represents the number of patients in each placebo arm analysed. Conclusion Placebo response rates are rising over time, in parallel to the change of geographic recruiting patterns, with more recent RCTs recruiting increasingly in less effluent countries. Our data support the hypothesis that these geographic recruitment changes are a significant contributor to the higher placebo rates observed in more recent clinical trials. One explanation may be the more limited access to health care and innovative therapies in less affluent countries, leading to preferential incentives for inclusion in clinical trials and subsequently also higher regression to the mean, which will be considered as placebo response. These effects should have implications for sponsors, investigators, patients, health care providers and political stakeholders. REFERENCES NIL Acknowledgements We thank the expert librarians, Mag.a Brigitte Wildner and Dr. Eva Chwala, for their assistance with the database searches. The authors also thank B. Bierbaumer, MSc for his assistance in building the underlying database for this project. Disclosure of Interests Andreas Kerschbaumer AbbVie, Amgen, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer and UCB, AbbVie, Amgen, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer and UCB, Marlene Steiner: None declared, Pascale Pruckner: None declared, Josef S. Smolen Samsung, Lilly, R-Pharma, Chugai, MSD Janssen, Novartis-Sandoz, Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly, Astra-Zeneca, Abbvie, Astra-Zeneca, Lilly, Galapagos, Daniel Aletaha Abbvie, Gilead, Janssen, Lilly, Merck, Novartis, Sanofi, Galapagos, Lilly.

Background Psoriatic arthritis (PsA) is a very heterogeneous disease; patient profiles in randomised controlled trials (RCTs) may not reflect patients from usual clinical practice. Objectives The objective was to compare characteristics of PsA patients between RCTs of biologic disease-modifying antirheumatic drugs (bDMARDs), and a real-world study recruiting over the same timeframe, PsABio. Methods Data sources: (a) Literature review and meta-analysis of phase III RCTs of bDMARDs in PsA published between 2015-2020; (b) International observational study of PsA patients starting a bDMARD enrolled in 2015–2018 (PsABio, NCT02627768)[1]. Data collected at baseline included swollen and tender joint counts (SJC, TJC), enthesitis, skin involvement (body surface area, BSA), and patient-reported outcomes (HAQ, pain). Meta-analysis was performed on RCT data, using the Mantel-Haenszel method with random effects. Results Overall, 10 RCTs (total 5654 participants) were analysed and compared to 930 PsABio participants (Table 1). Demographic data were similar across studies. SJC/TJC were higher in RCTs than in PsABio (pooled mean SJC/TJC 11.8/21.5, versus 5.7/11.9 respectively). Oligoarticular disease was not the focus in RCTS whereas in PsABio, 58% participants had oligoarticular disease. Enthesitis was also more frequent in RCTs (64.7% versus 48.2%). Patients with a BSA>3% were more frequent in RCTs (62.2% versus 54.0%). In contrast, patient-reported disease impact was high and similar in both data sources (HAQ 1.2 vs 1.1; pain 60mm vs 61mm) (Table 1). Overall, almost half (44%) of PsABio participants would not have fulfilled the RCT inclusion criteria due to too low disease activity. Conclusion RCTs largely represent patients with polyarticular, highly active PsA; in contrast, in routine clinical practice, many patients receiving biologics have mild/moderate joint disease, and often limited skin psoriasis. However, patients with PsA starting a bDMARD reported similar high disease impact both in RCTs and in the real-world PsABio study indicating a discordance between disease activity and disease impact. The interpretation of trials should take these elements into account. REFERENCES [1] Gossec L, et al. Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: Final 3-year results from the PsABio real-world study. Ann. Rheum. Dis. 2023;82:496–506.View this table: • View inline • View popup Table 1. Comparison of key baseline characteristics between a real-world study (PsABio) and pooled data from 10 bDMARD phase III RCTs. Acknowledgements NIL Disclosure of Interests Gelsomina Alle: None declared, Clementina López-Medina Abbvie, UCB, Janssen, Lilly, Novartis and MSD, Stefan Siebert AbbVie, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, Teijin Pharma and UCB., Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and UCB, Frédéric Lavie Johnson & Johnson, Wim Noel Johnson & Johnson, Johnson & Johnson, Josef S. Smolen AbbVie, Galapagos/Gilead, Novartis, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly, MSD, Janssen, AbbVie, Galapagos/Gilead, Novartis, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly, MSD, Janssen, AbbVie, Astra Zeneca, Lilly, Galapagos, Laure Gossec AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, AbbVie, Biogen, Lilly, Novartis, UCB

Background Idiopathic inflammatory myopathies (IIM) comprise a heterogenous group of autoimmune diseases characterised by inflammation of muscle and affection of other organs, such as lung or skin. A significant proportion of IIM patients have progressive weakness of the skeletal muscle as the predominant or sole clinical manifestation despite therapy. Response to treatment with glucocorticoids (GC) and immunosuppressive drugs varies substantially among patients and IIM-subtypes. However, some patients do not respond sufficiently to these therapies and, therefore, other treatment modalities have to be considered. There are only limited data on efficacy and safety of immunoglobulin removal by immunoadsorption (IAS) in patients with refractory IIM. Objectives We aimed to assess IAS efficacy and safety in management of therapy-refractory IIM-patients. Methods In this monocentric retrospective study, we evaluated the effects of IAS in IIM patients with predominantly muscular involvement, and previous non-response to GC or/and ≥1 immunomodulating drug. IAS was performed via columns using Protein A, Globaffin or Ig Therasorb columns with polyclonal sheep antibodies to eliminate immunoglobulin G from circulation. In a single treatment session, a total plasma volume of 6000-8000 ml was processed. The frequency of IAS sessions was on average 2.3 sessions per week. The primary endpoint was a minor improvement, defined as ≥20% reduction in daily GC dosage and ≥20% decline in creatine kinase (CK) after 4 weeks. Secondary endpoints included moderate and major improvement (reduction in daily GC dosage and CK-values of ≥40% and ≥60%, respectively) at weeks 4, 8, and 12. We further assessed relapse rates during the 3-month period following the last IAS procedure. A sensitivity analysis was performed using a last observation carried forward method addressing missing values. Results Between 2000 and 2021, 25 IIM patients treated with IAS were identified; 23 of them fulfilled the inclusion criteria and were evaluated. Patient characteristics at start of IAS are shown in Table 1. At week 4, 43.5% (n=10) of IIM patients achieved the primary endpoint of minimal improvement. Secondary endpoints, such as moderate improvement was observed in 10 patients (43.5%) at week 4, and a major improvement was noted in 12 patients (52.2%) at week 4. Further rates of clinical response are shown in Figure 1. The daily dosage of oral glucocorticoids decreased by 14.3% at week 4 as well as week 8, and by 20% at week 12 after initiation of IAS. Reduction from baseline in creatine kinase levels was maximal at week 8 (84.3%). Among the 6 seronegative patients, 5 (83%) were non-responders, while 53% of the 17 patients presenting with any autoantibody were responders. No unexpected adverse safety or tolerability issues were observed. Relapses occurred only in about 20% within three months after cessation, however the rate of relapses was higher in those without initial response at week 4. Conclusion IAS may serve as efficacious adjunctive therapy in seropositive IIM-patients who are refractory to GC and conventional treatments, leading to rapid reduction CK levels and allowing a decrease of GC dosage despite their previously non-responsive state. Table 1 Cohort descriptives • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Figure 1. Clinical response categories. Red (minor improvement), yellow (moderate improvement), blue (major improvement) REFERENCES NIL Acknowledgements NIL Disclosure of Interests None declared