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ObjectivesTo determine the incidence of osteoarthrits (OA) in patients with atopic disease compared with matched non-exposed patients.MethodsWe conducted a retrospective cohort study with propensity score matching using claims data from Optum’s de-identified Clinformatics Data Mart (CDM) (January 2003 to June 2019) and electronic health record data from the Stanford Research Repository (STARR) (January 2010 to December 2020). We included adult patients without pre-existing OA or inflammatory arthritis who were exposed to atopic disease or who were non-exposed. The primary outcome was the development of incident OA.ResultsIn Optum CDM, we identified 117 346 exposed patients with asthma or atopic dermatitis (mean age 52 years; 60% female) and 1 247 196 non-exposed patients (mean age 50 years; 48% female). After propensity score matching (n=1 09 899 per group), OA incidence was higher in patients with asthma or atopic dermatitis (26.9 per 1000 person-years) compared with non-exposed patients (19.1 per 1000 person-years), with an adjusted odds ratio (aOR) of 1.58 (95% CI 1.55 to 1.62) for developing OA. This effect was even more pronounced in patients with both asthma and atopic dermatitis compared with non-exposed patients (aOR=2.15; 95% CI 1.93 to 2.39) and in patients with asthma compared with patients with chronic obstructive pulmonary disease (aOR=1.83; 95% CI 1.73 to 1.95). We replicated our results in an independent dataset (STARR), which provided the added richness of body mass index data. The aOR of developing OA in patients with asthma or atopic dermatitis versus non-exposed patients in STARR was 1.42 (95% CI 1.36 to 1.48).ConclusionsThis study demonstrates an increased incidence of OA in patients with atopic disease. Future interventional studies may consider targeting allergic pathways for the prevention or treatment of OA.

Background:Despite the clinical benefits of current pharmacological treatments for rheumatoid arthritis (RA), there remains an unmet need for alternative treatment approaches. Initial results of a 12-week proof-of-concept study of non-invasive, vagus nerve stimulation (VNS) of the auricular branch of the vagus nerve from a wearable device to treat RA showed the device to be well-tolerated with significant reductions in the DAS28-CRP and RA disease severity1.Objectives:This analysis presents data from the 9-month extension of the original proof-of-concept study.Methods:Following the completion of the 12-week proof-of-concept study, responding patients (defined as achieving a reduction in DAS28-CRP of ≥1.2 from baseline and/or achievement of ACR20) were given the option to enroll in a 9-month extension study. Use of the wearable device continued daily for up to 30 minutes as in the first 12 weeks of the study. Alteration of baseline medication and addition of conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs were allowed during the extension phase.Results:20/27 patients who completed the initial 12-week study met the enrollment criteria for the extension phase; 19 of those patients consented to participate. 4/19 patients (21%) discontinued the extension study due to lack of efficacy (1 patient after 1 month, 2 patients after 3 months, and 1 patient after 6 months in the extension); 15 patients completed the extension phase. 2/15 patients (13%) added biologic therapy to their treatment regimen. Mean DAS28-CRP reduction from baseline to the end of the extension (12 months total) in all patients completing the extension was 2.23 (95% CI: -1.60, -2.86). For patients who did and did not add biologic therapy, mean DAS28-CRP reduction was 2.98 and 2.11, respectively. Individual DAS28-CRP reductions are shown in the figure 1. Mean HAQ-DI reduction from baseline to the end of the extension in all patients was 0.70. 2 non-device related adverse events were reported in the study extension: one related to cornea transplant and one related to dysesthesia. No serious adverse events were reported during the study extension phase.Conclusion:Benefits from the use of the wearable device were maintained over longer periods of time from the initial 12-week proof-of-concept study, with few safety concerns as no additional side effects were observed.References:[1]Marsal S et al. Non-invasive Vagus Nerve Stimulation Improves Signs and Symptoms of Rheumatoid Arthritis: Results of a Pilot Study [in press]. The Lancet Rheumatol, 2021Disclosure of Interests:Sara Marsal Speakers bureau: BMS, Pfizer, UCB, Celgene, Roche, Sanofi, Consultant of: Pfizer, Abbvie, Roche, Celgene, Galapagos, MSD, UCB, BMS, Sanofi, Grant/research support from: Pfizer, Abbvie, Roche, Celgene, MSD, UCB, BMS, Novartis, Janssen, Sanofi, Héctor Corominas: None declared, Juan Jose de Agustin: None declared, Carolina Perez-Garcia: None declared, Maria Lopez Lasanta: None declared, Helena Borrell Paños: None declared, D Reina-Sanz: None declared, Raimón Sanmartí: None declared, J. Narváez: None declared, Clara Franco-Jarava: None declared, Charles Peterfy Speakers bureau: Novartis, Bristol Myers Squibb, Amgen, Consultant of: Multiple companies on behalf of Spire Sciences Inc., Jose Antonio Narvaez: None declared, Vivek Sharma Shareholder of: Nēsos Corp, Employee of: Nēsos Corp, Konstantinos Alataris Shareholder of: Nēsos Corp, Employee of: Nēsos Corp, Mark C. Genovese Shareholder of: Gilead Sciences, Nēsos Corp, Employee of: Gilead Sciences, Matthew Baker Shareholder of: Nēsos Corp, Consultant of: Nēsos Corp

Background:IgG4-related disease (IgG4-RD) is an immune-mediated disorder causing fibro-inflammatory lesions. Although the cause remains unknown, it may be driven by interactions between B lymphocytes and CD4+ cytotoxic and regulatory T cells and is characterized by an increase in short-lived plasmablasts, circulating antibodies, and macrophages. Standard therapy mainly includes glucocorticoids (GC), limited by toxicity with long-term use (> 6 mo), and to a lesser extent, immunosuppressives (eg, rituximab). Bruton tyrosine kinase (BTK) plays an important role in the activation of multiple immune effector cells such as B cells, mast cells, eosinophils, basophils, monocytes/macrophages, and neutrophils. Dysregulation of the activation of these immune cells results in autoimmune inflammation, tissue damage, and development of fibrosis. Rilzabrutinib is a highly selective oral BTK inhibitor that targets multiple pathways of innate and adaptive immunity (with direct effects on B-cell and FcR pathways) and has the potential to inhibit antigen presentation to autoreactive T cells.Objectives:To provide the biological rationale for rilzabrutinib in IgG4-RD.Methods:Rilzabrutinib has been evaluated in biochemical, in vitro studies, and in vivo models of inflammatory diseases. Additional support is provided by the phase 2 trial for oral rilzabrutinib in patients with pemphigus vulgaris and the phase 2 trial for oral rilzabrutinib in patients with immune thrombocytopenia (ITP).Results:Rilzabrutinib inhibited the activity of BTK and B-cell receptor in B cells (IC50 5-123 nM) and Fc gamma receptor in IgG/Fc gamma receptor-stimulated monocytes (IC50 56 nM) and blocked IgG- and IgM-mediated antibody production in enriched B cells when stimulated in T-cell dependent (anti-CD40+IL-21) and T-cell independent (TLR-9/CpG and TNP-LPS) pathways. The impact of rilzabrutinib on innate cell pathways was further confirmed by significant dose-dependent inhibition of macrophage and neutrophil-driven passive rat Arthus reaction (P < 0.01 vs vehicle) and antibody-induced murine ITP (P < 0.05 vs vehicle). In a 12-week phase 2 pemphigus vulgaris trial, 54% of patients achieved the primary endpoint, control of disease activity (CDA) on low-dose corticosteroids by week 4, and 73% achieved it by week 12. In the phase 2 trial of ITP patients (median 6 prior therapies), rilzabrutinib 400 mg bid showed rapid and sustained improvement in platelet counts and only grade 1/2-related adverse events1. In responders, platelet counts increased as early as day 8, potentially due to innate immune mechanisms. Collectively, results in both B and innate immune cells provide an initial basis for evaluating rilzabrutinib in IgG4-RD. The ongoing phase 2a study (NCT04520451) is investigating rilzabrutinib 400 mg bid (+tapered GC) vs GC control (3:1) for 12 weeks in IgG4-RD patients refractory to rituximab. The primary objective is to evaluate the safety and ability of rilzabrutinib to induce GC-free remission at week 12. Coupled with known preclinical/clinical findings, mechanistic analyses in this ongoing IgG4-RD study will profile B and other immune cell effects pre-/post-rilzabrutinib dosing to enhance the clinical understanding of rilzabrutinib in IgG4-RD.Conclusion:Studies of rilzabrutinib that show beneficial effects on both B-cell and innate cell pathways provide support for its therapeutic role in immune-mediated diseases and for targeting the underlying pathophysiological effects of IgG4-RD. Effective and safe therapies that rapidly induce and maintain clinical responses, while minimizing the need for continuous GC treatment, remain an unmet need for patients with IgG4-RD.References:[1]Kuter et al. Res Pract Thromb Haemost. 2020;4(suppl 1): PB1318.Disclosure of Interests:Li Long Employee of: Principia Biopharma, a Sanofi Company, Matthew Baker: None declared, Mollie Carruthers: None declared, Alireza Meysami: None declared, Robert Spiera Consultant of: research funding and personal fees for consulting from Chemocentryx, Formation Biologics, Roche-Genentech, and Sanofi, Grant/research support from: research funding fees from BMS, Boehringer Ingelheim, Corbus, GSK, and Inflarx; personal fees from AbbVie, CSL Behring, GSK, and Janssen, Mamatha Reddy Employee of: Principia Biopharma, a Sanofi Company, Marianne Kavanagh Employee of: Principia Biopharma, a Sanofi Company, Michelle Francesco Employee of: Principia Biopharma, a Sanofi Company, Claire Langrish Employee of: Principia Biopharma, a Sanofi Company, Ann Neale Employee of: Principia Biopharma, a Sanofi Company, Puneet Arora Employee of: Principia Biopharma, a Sanofi Company, John H. Stone Consultant of: research funding and personal fees for consulting from Principia and Sanofi

ObjectivesPatients with lupus membranous nephropathy (LMN) are at risk for prolonged proteinuria and progressive chronic kidney disease. There are no proven effective treatments for LMN, and controlled trials are lacking. This trial assessed the preferential Janus kinase 1 (JAK1) inhibitor filgotinib and the spleen tyrosine kinase inhibitor lanraplenib in patients with LMN.MethodsThis was a phase II, randomised, double-blind trial conducted at 15 centres in the USA to evaluate the safety and efficacy of filgotinib or lanraplenib for the treatment of LMN. Eligible patients were randomised 1:1 to receive either filgotinib or lanraplenib in a blinded fashion for up to 52 weeks. The primary endpoint was the per cent change in 24-hour urine protein from baseline to week 16.ResultsNine patients were randomised to receive filgotinib (n=5) or lanraplenib (n=4). Four patients in the filgotinib group and one patient in the lanraplenib group completed week 16. There was a median reduction of 50.7% in 24-hour urine protein after 16 weeks of treatment with filgotinib (n=4), and the median Systemic Lupus Erythematosus Disease Activity Index from the Safety of Estrogens in Lupus National Assessment score remained stable. Filgotinib treatment was well tolerated. Limited conclusions can be drawn about treatment with lanraplenib.ConclusionThe number of patients treated in this study was small, and only limited conclusions can be drawn. There may be a therapeutic benefit with filgotinib treatment, which may support future investigations with filgotinib or other JAK inhibitors in patients with LMN.Trial registration numberNCT03285711.

Background:Despite the clinical benefit of current pharmacological treatments for rheumatoid arthritis (RA), there remains an unmet need for alternative treatment approaches. Vagus nerve stimulation (VNS) via an implanted device has been shown to attenuate RA disease severity in patients resistant to therapy,1as evidenced by a reduction in the DAS28-CRP score following a month of daily stimulation.Objectives:This pilot study investigated the safety and efficacy of a wearable (non-invasive) device that attaches to the outer ear to treat RA via electrical stimulation of the auricular branch of the vagus nerve.Methods:Patients with active RA (≥4 tender/swollen joints based on a 28-joint count, Disease Activity Score-28 with C-reactive protein (DAS28-CRP) >3.8, active synovitis detected on ultrasound and MRI) and inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), or csDMARD and biologic DMARDs (bDMARDs), were enrolled in this open-label study. Patients used the device for up to 30 minutes daily over the course of the 12-week study. The primary endpoint was the change in DAS28-CRP score at Week 12. Secondary endpoints included a safety analysis, proportion of patients achieving ACR20/50/70, the mean change in HAQ-DI and the proportion of patients achieving a HAQ-DI MCID of at least 0.22 over 12 weeks. Additionally, sleep scores were assessed using a visual analogue scale (0-100) at baseline and 12 weeks.Results:Thirty patients with active RA were enrolled, of which 27 patients completed the 12-week protocol. Three patients dropped out of the study: two patients decided to seek other treatment and one patient moved out of the country. Data for three additional patients was not included in this dataset as it was still being collected. Of the 24 patients with complete 12-week datasets, 88% were female, the average age was 54.9 years, mean disease duration was 7.3 years, and four patients had an inadequate response to one or two bDMARDs.The mean change in DAS28-CRP from baseline to Week 12 was -1.43 (pFigure 1Figure 2Average DAS28-CRP is shown for each study visit. Error bars indicate standard error of mean. Percentage of subjects meeting ACR20/50/70 at 12 weeks.Conclusion:In this pilot study, auricular stimulation was well tolerated and daily use over 12 weeks attenuated RA disease severity. Further evaluation in larger controlled studies are needed to confirm whether a non-invasive wearable device might offer an alternative approach for the treatment of RA.References:[1]Koopman FA, et al. (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Nat Acad Sci 2016; 113: 8284–9.Disclosure of Interests:Sara Marsal: None declared, Héctor Corominas Speakers bureau: Abbvie, Lilly, Pfizer, Roche, Maria Lopez Lasanta: None declared, D Reina-Sanz: None declared, Carolina Perez-Garcia: None declared, Helena Borrell Paños Speakers bureau: Lilly, Novartis, MSD and Janssen, Raimón Sanmartí Speakers bureau: Abbvie, Eli Lilly, BMS, Roche and Pfizer, J. Narváez: None declared, Clara Franco-Jarava: None declared, Jose Antonio Narvaez: None declared, Juan Jose de Agustin: None declared, Vivek Sharma Shareholder of: Vorso Corp., Konstantinos Alataris Shareholder of: Vorso Corp., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Matthew Baker Consultant of: Gilead, Vorso, Paid instructor for: Gilead