OBJECTIVE:We aimed to develop expert consensus recommendations for musculoskeletal ultrasound (MSUS) education in Canadian rheumatology residency programs. METHODS:This three-stage consensus study used an international working group of 13 MSUS experts and 5 nonexpert stakeholders and incorporated cognitive load theory to ensure educational feasibility. In stage one, MSUS experts participated in a modified nominal group technique (NGT) to generate and prioritize items for stage two. In stage two, the working group completed three survey rounds using a modified Delphi technique, with consensus defined as agreement ≥70%. In stage three, experts reviewed items from stage two in a structured focus group, rating each for clinical utility, learnability, and feasibility of national implementation. RESULTS:The NGT generated 30 prioritized anatomic areas and pathologies. The Delphi working group represented 7 of 12 (58%) Canadian rheumatology programs (English stream) and two US experts. The response rate across all Delphi rounds was 100%. Round one included 83 items, round two included 52, and round three included 9. Consensus was reached on all but 5 items, yielding 42 core and 38 optional items. In the structured focus group, consensus was reached that all core items are clinically valuable, learnable for rheumatology residents, and feasible for national implementation. Core items were then organized into 33 MSUS competencies, encompassing general ultrasound skills; features of inflammatory arthritis in the hands, wrists, and metatarsophalangeal (MTP) joints; double contour sign in the MTP joints; and effusion detection in the knee and ankle joints. CONCLUSION:These recommendations provide a foundation for standardized MSUS curricula in rheumatology residency programs.

People with immune-mediated inflammatory diseases (IMIDs) may be more vulnerable to severe COVID-19 outcomes. COVID-19 vaccination is a key element in mitigating this risk. Anti-SARS-CoV-2 antibodies (Ab), including anti-spike (S) and anti-receptor binding domain (RBD) Ab, are metrics of seroconversion following COVID-19 vaccination in the general population. We assessed if anti-S and anti-RBD antibodies were negatively correlated with COVID-19 infection in IMID. SUCCEED, a prospective Canada-wide study, was conducted in 2 phases. First, between Feb 2021-Jul 2023, adult IMID participants provided dried blood spot samples for anti-S and anti-RBD ELISA testing at intervals of 1, 3, 6, and 12 months following each COVID-19 vaccine dose. Second, between Sep 2022-Aug 2023, consenting participants from 4 academic centers in British Columbia, Ontario and Quebec (2) also provided monthly saliva samples for PCR detection of SARS-CoV-2. We studied subjects receiving at least their primary series (3+ doses) of a COVID-19 vaccine. Multivariable general estimating equation (GEE) models (accounting for repeated measures) evaluated PCR SARS-CoV-2 detection in saliva, assessing the effects of anti-S or anti-RBD levels (in separate models) within the 6 months preceding a given saliva sample. We controlled for recent COVID-19 infection, sex, age, medications (conventional immunosuppressives, biologics, and prednisone), and time since last COVID vaccine. 366 participants contributed 1,266 saliva samples. Participants were 79.8% female and 85.5% White, with median age 56.7 (standard deviation: 13.8) years. Most participants were taking immunosuppressants (N=252, 68.9%). The majority (N=356, 97.3%) of participants displayed seroconversion at the first saliva sample, defined as ≥11.3 Binding Antibody Units (BAU)/ml for anti-S or ≥31 BAU/ml for anti-RBD. In the GEE models of positive saliva PCR for SARS-CoV-2, (Table 1) a 1000 BAU/ml increase in anti-S was associated with an adjusted odds ratio (aOR) of 0.66 (95% confidence interval [CI] 0.45-0.97). Anti-RBD Ab levels had a similar effect (aOR 0.91, 95% CI 0.81-1.02). Table 1: Odds Ratios, OR (95% confidence intervals, CI) for Having a Positive COVID-19 Saliva Test in Univariable and Multivariable GEE Models In this large, multi-center sample of COVID-19-vaccinated individuals with IMIDs, most of whom were immunosuppressed, we demonstrated that anti-S Ab levels were associated with lower odds of positive saliva PCR test for SARS-CoV-2, with a similar trend for anti-RBD Ab. This highlights clear benefits for vaccination against SARS-CoV-2 in IMID.

ObjectiveInterstitial lung disease (ILD) is a common and potentially lethal complication of systemic sclerosis (SSc). Screening by high-resolution computed tomography (HRCT) is recommended in all patients with risk factors, including early disease. Little is known on late presentations of ILD. This study aimed to characterize the incidence, risk factors, and outcomes of late-onset SSc-ILD.MethodsStudy participants enrolled in the Canadian Scleroderma Research Group cohort from 2004 to 2020 without prevalent ILD were included. Incidence and risk factors for ILD (on HRCT) were compared according to disease duration above (late) and below (earlier) seven years from the first non-Raynaud manifestation. Risk of ILD progression was compared using Kaplan-Meier and multivariable Cox models.ResultsOverall, 199 (21%) of 969 patients developed incident ILD over a median of 2.4 (interquartile range 1.2-4.3) years. The incidence rate in late SSc (3.7/100 person-years) was lower than in earlier SSc (relative risk 0.68, 95% confidence interval [CI] 0.51-0.92). Risk factors for incident ILD included male sex, diffuse subtype, myositis, antitopoisomerase I autoantibodies, and higher C-reactive protein levels. Patients with late-onset ILD were also less frequently White and more frequently had arthritis and anti-RNA-polymerase III autoantibodies. Lung disease severity was similar between late- and earlier-onset SSc-ILD (forced vital capacity 88% and 87%, diffusion capacity of the lungs for carbon monoxide 64% and 62%, respectively). Progression rates were also similar between late- and earlier-onset SSc-ILD (log rank P = 0.8, hazard ratio 1.11, 95% CI 0.58-2.10).ConclusionILD can present in late SSc. Risk factors and progression rates overlapped with earlier-onset SSc-ILD. Surveillance for ILD should continue in longstanding SSc. Frequency and modality of monitoring remain to be defined.

Vaccines rely on a global cold chain to maintain vaccine potency throughout the product life cycle. Existing vaccine thermostabilization methods like lyophilization and spray-drying impart significant stress on the vaccine, reducing its potency. Therefore, dissolvable oral thin films (OTFs) have emerged as an alternative thermostabilizing vaccine delivery platform wherein the vaccine is immobilized in a polymer-sugar matrix and administered to the oral mucosa. Herein, we demonstrate the feasibility of incorporating a model adenovirus vector into an OTF (Ad5 OTF) using a simple one-hour solvent casting process, and we demonstrate retention of the adenovirus infectious titer during storage, as assessed by flow cytometric titering. Increasing Tris buffer concentration and changing the surfactant from a nonionic Tween 80 to a zwitterionic poly(maleic anhydride-alt-1-octadecene) substituted with 3-(dimethylamino)propylamine (PMAL) and increasing its concentration improved the six-day ambient temperature stability by nearly 4-fold. A 23 full factorial design of experiment investigating the influence of PMAL, trehalose, and PEG concentration demonstrated that PMAL and trehalose concentration have the greatest impact on stability of Ad5 OTFs, improving the six-day ambient temperature stability by 250-fold, compared to the first formulation evaluated herein. The thermal stabilization of Ad5 OTFs prepared with a simple one-hour casting process demonstrates the scale-up and scale-out potential for this OTF formulation as a vaccine delivery platform, improving the accessibility of vaccines.

BACKGROUND:Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy. METHODS:Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment. RESULTS:PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment. CONCLUSION:This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.

OBJECTIVE To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.

Background: CD19+CD27-IgD- Double Negative (DN) B cells identified in severe acute-COVID (PMID: 33028979) may underlie the autoimmune responses in post-acute COVID-19 sequalae (PACS) (PMID: 36137590). Aims: We aimed to investigate the B cell profile in well-characterised PACS patients and their associated symptoms. Methods: Circulating B cells were immunophenotyped by flow cytometry from 17 PCR+ PACS patients (WHO guidelines, ≥18 years, no history of autoimmune disease) and 8 healthy controls (HC) (NCT:05459506). Results: Out of 17 PACS (mean age 41, 13 females, median length post-recovery 11.3 months) commonly reported symptoms were fatigue (65%), joint pain and myalgia (63%), dyspnea (59%) and dry cough (35%). No difference was seen in the B cell-subsets between PACS and HC except for an increased trend in DN B cells (Fig1A). DN B cells were increased in patients with ≥6 reported symptoms (Fig1B). Further characterized, DN2 (CD11c+CD21-) and DN3 (CD11c-CD21-) cells (reported in autoimmune diseases and severe acute COVID-19 respectively), were positively associated with increased PACS symptoms (Fig1C). Three patients with high DN B cells developed autoimmune disease (vitiligo, lupus, and postural orthostatic tachycardia syndrome). Conclusion: DN B cells are elevated in PACS patients, specifically those experiencing persistent joint pain, myalgia, and fatigue and may direct rheumatological trajectories post-COVID.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. In addition to anti-platelet autoantibodies, CD8(+) T cells have been implicated as a mechanism of platelet destruction. The current evidence for the existence of platelet-specific CD8(+) T cells in ITP is inconclusive. The purpose of this review is to summarize the studies that investigated CD8(+) T cells in ITP and to review the methods that have been used to detect autoreactive CD8(+) T cells in other autoimmune diseases.

Background: Infliximab is a monoclonal antibody that binds and neutralizes circulating tumor necrosis factor-alpha, a key inflammatory cytokine in the pathophysiology of sarcoidosis. Despite the paucity of randomized clinical trials, infliximab is often considered a therapeutic option for refractory disease. Our study aimed to investigate the effectiveness of infliximab in patients with refractory sarcoidosis. Methods: Sarcoidosis patients from three tertiary centres were retrospectively identified by pharmacy records based on treatment with infliximab. Treatment with Infliximab was initiated in patients who failed first and second line immunomodulators as determined by a multidisciplinary team of Respirologists, Dermatologists, ENT specialists, Rheumatologists, and Neurologists. Participants were characterized by the primary organ for which infliximab was initiated and the total number of organs involved. Clinical outcomes were categorized as treatment success versus failure. We defined treatment success as (A) improvement of cutaneous, upper airway, lymph node, gastrointestinal, eye, or joint manifestations; or (B) improvement or no change in central nervous system (CNS) or pulmonary manifestations. Results: 33 patients with refractory sarcoidosis were identified. The proportion of treatment success was 100% (95% CI 54.1-100) in CNS, 91.7% (95% CI 61.5-99.8) in cutaneous, 78.6% (95% CI 49.2-95.3) in pulmonary and 71.5% (95% CI 29.0-96.3) in upper airway disease. The use of infliximab was associated with a reduction prednisone dose by 50%. Conclusion: Infliximab is possibly an effective therapy for refractory sarcoidosis, with the greatest value in neurologic and cutaneous manifestations. Across all disease presentations, infliximab facilitated a clinically relevant reduction in corticosteroid dose. Relapse is common after discontinuation of infliximab.

BackgroundA Treat-to-Target approach (T2T) is broadly considered to lead to better clinical outcomes and recommended in patients with RA. However, very few studies have analyzed the effect of T2T on radiographic progression, and any such studies have provided inconsistent results.ObjectivesTo investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice leads to lower radiographic progression in RA.MethodsPatients from the multicenter RA-BIODAM cohort with ≥2 consecutive visits with radiographs available were included. In RA-BIODAM patients were enrolled as they were initiating a new csDMARD/bDMARD treatment were followed-up with the intention to benchmark and intensify treatment. The primary outcome of this analysis was the change in Sharp-van der Heijde score (SvdH, 0-448), assessed every 6 months, using average scores from 2 readers (scores with known chronological order). Following a DAS44-T2T remission strategy, which was defined at each 3-month visit, was the main variable of interest. Patients were categorized based on the proportion of visits in which T2T was followed according to our definition: very low (≤40% of the visits, low (>40%, <62.5%), high (≥62.5%, ≤75%) and very high (>75%). Radiographic progression at 2 years was visualized across groups by cumulative probability plots. Per 3-month interval T2T could be followed zero, one or two times (in a total of 2 visits). Associations between the number of visits with T2T in an interval and radiographic progression, both in the same and in the subsequent 6-month interval, were analysed by generalised estimating equations, adjusted for age, gender, disease duration and country.ResultsIn total, 511 patients were included (mean (SD) age: 56 (13) years; 76% female). After 2 years, patients showed on average 2.2 (4.1) units progression (median:1 unit). Mean (SD) 2-year progression was not significantly different across categories of T2T: very low: 2.1 (2.7)-units; low: 2.8 (6.0); high: 2.4 (4.5), very high: 1.6 (2.2) (Figure 1). Meticulously following-up T2T in a 3-month interval neither reduced progression in the same 6-month interval (parameter estimates (for yes vs no): +0.15 units (95%CI: -0.04 to 0.33) for 2 vs 0 visits; and +0.08 units (-0.06;0.22) for 1 vs 0 visits) nor did it reduce progression in the subsequent 6-month interval (Table 1).Table 1.Effect of following DAS44-remission-T2T strategy on 6-month radiographic progression over 2 yearsChange in radiographic damage(regression coefficient (95% CI))N=506T2T during 3 months on radiographic progression in the same 6-month period 2 visits vs 0 followed0.15 (-0.04; 0.33) 1 visit vs 0 followed0.08 (-0.06; 0.22)T2T during 3 months on radiographic progression in the subsequent 6-month period 2 visits vs 0 followed-0.09 (-0.28; 0.10) 1 visit vs 0 followed-0.10 (-0.24; 0.05)Figure 1.Cumulative probability plot with 2-year radiographic progression according to the proportion of 3-monthly visits with T2T followedConclusionIn this daily practice cohort, more meticulously following T2T principles did not result in more reduction of radiographic progression than a somewhat more liberal attitude toward T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome.AcknowledgementsBIODAM was financially supported by an unrestricted grant from AbbVieDisclosure of InterestsSofia Ramiro Speakers bureau: Eli Lilly, MSD, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, Pfizer, UCB, Sanofi, Grant/research support from: AbbVie, Galapagos, Novartis, Pfizer, UCB, Robert B.M. Landewé Speakers bureau: AbbVie, BMS, Gilead, Galapagos, GSK,Janssen, Lilly, Novartis, Pfizer, UCB, Consultant of: AbbVie, BMS, Gilead, Galapagos, GSK,Janssen, Lilly, Novartis, Pfizer, UCBDr Landewé owns Rheumatology Consultancy BV, Désirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer, UCB Pharma. Director of Imaging Rheumatology bv., Alexandre Sepriano Speakers bureau: Novartis, Consultant of: UCB, Oliver FitzGerald Speakers bureau: Biogen, Novartis, AbbVie, BMS, Pfizer, Grant/research support from: BMS, Novartis, UCB, Pfizer, Lilly, Janssen, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Orion, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, Amgen, BMS, Merck, Celgene and Novartis, Joanne Homik: None declared, Ori Elkayam Speakers bureau: Pfizer, Lilly, Novartis, Abbvie, BI, Janssen, Consultant of: Pfizer, Lilly, Novartis, Abbvie, BI, Janssen, Grant/research support from: Pfizer, Abbvie, Janssen, Carter Thorne Consultant of: Abbvie, Organon, Pfizer, Sandoz, Maggie Larché Speakers bureau: AbbVie, Actelion, Amgen, BMS, Boehringer-Ingelheim, Fresenius-Kabi, Gilead, Janssen, Mallinckrodt, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi, UCB, Grant/research support from: Abbvie, BMS, Gianfranco Ferraccioli Speakers bureau: SOBI, Consultant of: Abbivie, Marina Backhaus: None declared, Gilles Boire Speakers bureau: Abbvie Canada, BMS Canada, Lilly Canada, Janssen Canada, Merck Canada, Pfizer Canada, Viatris, Consultant of: Abbvie Canada, Amgen Canada, BMS Canada, Celgene, GileadSciences, Janssen Canada, Lilly Canada, Merck Canada, Mylan Canada, Novartis Canada, Pfizer Canada, Roche Canada, Samsung Bioepis, Sanofi Canada, Teva, Grant/research support from: Lilly Canada, BMS Canada, Pfizer, Sandoz Canada, UCB Canada, Merck Canada, Novartis Canada, Roche Canada, Bernard Combe Speakers bureau: Abbvie, BMS,Celltrion,Galapgos-Gilead, Janssen, Lilly, MERCK, Pfizer,Roche-Chugai, Consultant of: Abbvie, Celltrion,Galapgos-Gilead, Janssen, Lilly, MERCK, Roche-Chugai, Grant/research support from: Pfizer, Roche-chugai, Thierry Schaeverbeke: None declared, Alain Saraux Speakers bureau: Abbvie, Lilly, Nordic, Novartis, Pfizer, Roche-Chugai, Sanofi, UCB, Consultant of: Abbvie, Lilly, Nordic, Novartis, Pfizer, Roche-Chugai, UCB, Grant/research support from: Novartis, Fresenius, Lilly, Maxime Dougados Consultant of: Pfizer, AbbVie, UCB, Merck, Lilly, Novartis, BMS, Galapagos, Biogen, Roche, Grant/research support from: Pfizer, AbbVie, UCB, Merck, Lilly, Novartis, BMS, Galapagos, Biogen, Roche, Maurizio Rossini Speakers bureau: Amgen, Abbvie, BMS, Eli-Lilly, Galapagos,MSD, Novartis, Pfizer, Sandoz, Theramex, UCB, Marcello Govoni Speakers bureau: Abbvie, Pfizer, Galapagos, BMS, Eli-Lilly, Paid instructor for: Pfizer, Consultant of: Abbvie, BMS, Novartis, Astrazeneca, Pfizer, Luigi Sinigaglia: None declared, Alain Cantagrel Speakers bureau: Abbvie, Amgen, Biogen, BMS, Janssen, Lilly France, Médac, MSD France, Nordic-Pharma, Novartis, Pfizer, Sanofi Aventis, UCB, Consultant of: BMS, Janssen, Lilly France, MSD France, Sandoz, Grant/research support from: MSD France, Novartis, Pfizer, Cornelia Allaart: None declared, Cheryl Barnabe Speakers bureau: Sanofi Genzyme, Pfizer, Fresenius Kabi, Janssen, Consultant of: Gilead, Celltrion Healthcare, Clifton Bingham Consultant of: AbbVie, BMS, Eli Lilly, Janssen, Moderna, Pfizer, Sanofi, Grant/research support from: BMS, Dirkjan van Schaardenburg: None declared, Hilde Berner Hammer Speakers bureau: AbbVie, Novartis, Lilly, Rana Dadashova: None declared, Edna Hutchings: None declared, Joel Paschke: None declared, Walter P Maksymowych Speakers bureau: Abbvie, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Boehringer Ingelheim, Celgene, Eli-Lilly, Galapagos, Novartis, Pfizer, UCB, Grant/research support from: Abbvie, Novartis, Pfizer

Dr. Larche has nothing to disclose.