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Background:RA is an inflammatory disease that results in pain and loss of function, especially in the hands and wrists. Brief self-assessment tools that can reliably and precisely quantify hand/wrist function are needed to assess inflammatory activity when a physical exam is not feasible and to capture day-to-day experience of living with RA. Neuro-QoL is part of the PROMIS family of self-report measures created using a patient-centred approach and IRT methodology. The Neuro-Qol Upper Extremity Function (UEF) scale measures ability across fine motor and ADLs involving digital, manual and reach-related function and self-care. Little is known about its performance in RA.Objectives:To evaluate the validity and responsiveness of the 8-item Neuro-QoL UEF in RA. We hypothesized scores would be strongly (r>.70) associated with MHAQ, MD-HAQ, and PROMIS PF, moderately (r=.4 to .7) to symptoms, disease activity, and QoL indicators, and be responsive to change in disease activity and PF.Methods:Data were from the 0 and 6-month visits of adults with early RA (sx <1 yr) enrolled in the Canadian Early Arthritis Cohort, a prospective real-world study at 16 sites across Canada. Participants completed the Neuro-QoL UEF, MHAQ, MDHAQ, PROMIS-29, and PT Global at each visit. Rheumatologists recorded joint counts and MD Global. To evaluate content validity, we examined descriptive statistics across CDAI disease activity levels, and Pearson correlations between the Neuro-QOL UEF, legacy measures, CRP & ESR. Responsiveness was assessed by correlating change scores from visits 0-6 between Neuro-QoL UEF, disease activity and legacy PF scores.Results:The 262 participants were mostly white (83%) women (71%) with a mean (SD) age of 55 (13). Summary statistics at 6-months are shown in Table 1. Neuro-QOL UEF was moderately-strongly correlated with MHAQ, MDHAQ, PROMIS-PF (|r|=.63-.75) and moderately correlated with pain and stiffness, (|r|=.59, -.64), and CDAI, SDAI, PT&MD Global, TJ & SJ (|r|=.39-.58). Neuro-QOL UEF was moderately correlated with PROMIS QoL domains Pain, Fatigue, Anxiety, Depression, Sleep & Participation (|r|=.39-.60).Table 1.Summary statistics of physical function and RA disease activity indices at 6 months.MeanSDMdn25%75%(Min, Max)Physical FunctionNeuro-Qol UEF46.59.753.837.553.8(21.8, 53.8)MHAQ (0-3)0.290.430.130.000.38(0.00, 2.25)MD-HAQ (0-10)1.391.640.700.002.00(0.00, 8.00)PROMIS-PF46.48.546.239.556.0(23.3, 56.0)RA Disease ActivityCDAI9.39.96.03.013.0(0.0, 56.0)SDAI10.710.96.83.115.2(0.0, 57.0)Patient Global3.02.5315(0, 10)MD Global1.82.2103(0, 9)Swollen Joints (28)2.13.7002(0, 20)Tender Joints (28)2.43.9103(0, 24)Neuro-QOL scores decreased in a dose-response manner across worsening CDAI DA states reflecting increasing impairment (Table 2). Persons with HDA reported the highest disability, scoring nearly 0.5 SD lower on the Neuro-QoL UEF than PROMIS PF. Change from baseline to 6 months in Neuro-QoL UEF was moderately correlated with changes in PROMIS PF, MHAQ, PT Global, and CDAI (|r|=.44-.65). The mean change and range from 0-6 months in Neuro-QoL was significantly larger than in PROMIS (8.9 [95% CI 7.5, 10.4] vs. 5.4 [95% CI 4.4, 6.4])(see Figure).Table 2.Mean scores (95% CI) at 6 months by CDAI level.REMLDAMDAHADNeuroQol UEF52.8 (51.8, 53.7)48.1 (46.6, 49.7)42.0 (39.4, 44.6)33.8 (30.5, 37.1)MHAQ (0-3)0.05 (0.02, 0.09)0.19 (0.14, 0.24)0.45 (0.34, 0.57)0.90 (0.63, 1.17)MD-HAQ (0-10)0.31 (0.17, 0.46)1.11 (0.90, 1.32)2.15 (1.71, 2.59)3.56 (2.56, 4.56)PROMIS-PF52.8 (51.4, 54.2)46.8 (45.3, 48.2)42.3 (40.4, 44.2)38.0 (34.4, 41.6)Conclusion:Clinicians, researchers, and patients benefit from practical self-report tools that reliably and precisely monitor hand function in RA. Results offer initial evidence of validity and responsiveness and support use of Neuro-QoL UEF to self-assess inflammatory activity in the hands and day-to-day experiences of living with RA.Acknowledgements:The CATCH study was designed and implemented by the investigators and financially supported through unrestricted research grants from: Amgen and Pfizer Canada - Founding sponsors since January 2007; AbbVie Corporation and Hoffmann-LaRoche since 2011; Medexus Inc. since 2013;, Merck Canada since 2017, Sandoz Canada, Biopharmaceuticals since 2019,Gilead Sciences Canada since 2020 and Fresenius Kabi Canada Ltd. since 2021. Previously funded by Janssen Biotech from 2011-2016, UCB Canada and Bristol-Myers Squibb Canada from 2011-2018, Sanofi Genzyme from 2016-2017, and Eli Lilly Canada from 2016-2020.Disclosure of Interests:None declared

Background: CD4 T cells help B cells produce antibodies following antigen challenge. This response classically occurs in germinal centers (GC) located in B-cell follicles of secondary lymphoid organs (SLO), a site of immunoglobulin isotype switching and affinity maturation. GC formation requires specialized CD4 T cells, T-follicular helper (Tfh) cells, which localize to follicles and provide B cells with survival and differentiation signals that are essential for B-cell maturation into memory and long-lived plasma cells. Pathogenic autoantibodies in human and murine lupus arise in a like manner. Although Tfh cells are critical for GC development, their genesis in humans, role in promotion of autoimmunity, and potential as therapeutic targets in SLE are incompletely understood. To address these issues, we dissected Tfh cell development and function, defining their transcriptional regulation, migration, and function in vivo in normal and lupus-prone mice and ex vivo in normal humans and patients with SLE. Methods: We used a combination of approaches-flow cytometry, confocal microscopy, microarrays, quantitative chromatin immunoprecipitation and DNA sequencing (ChIP-seq), retroviral overexpression, and T-cell-B-cell helper assays-to characterize Tfh cells in normal mice and in lupus-prone strains, and from the tonsils of normal humans and the blood of patients with SLE. Results: We found that the transcription factor Bcl6 (B-cell CLL/lymphoma 6) is necessary and sufficient for Tfh development and function, via genetic control of Tfh proteins that are essential for their migration to B-cell follicles and GC and subsequent B-cell maturation. We dissected steps in Tfh development within SLO, beginning with their genesis in the T-cell zone followed by emigration to sites of B-cell interaction outside the B-cell follicle, where we have shown that B cells serve to provide signals for continued Tfh expansion and follicular migration. We have now begun to tease apart the factors that mediate T-cell-B-cell collaboration in the follicle; these represent therapeutic targets in SLE. Finally, we have shown that patients with SLE have expansion of Tfh cells in the blood, a finding that highlights their potential role in the pathogenesis of SLE and as likely therapeutic targets. Conclusion: These studies help define the developmental pathways for Tfh cells, and the steps that enable these cells to function in the B-cell follicle to promote immunoglobulin and autoantibody production. They have also helped define markers of Tfh cells in normals and autoimmune individuals, and suggest that they are a promising therapeutic target in patients.

BackgroundEarly RA is characterized by multiple symptoms that impact daily function and HRQL. Little is known about whether there are symptom clusters evident at diagnosis that could identify patients with a poorer prognosis, or the stability of clusters over time.ObjectivesTo identify patient-reported symptom clusters at RA diagnosis, associated sociodemographic and RA characteristics, and the stability of clusters over the first 6 months.MethodsUsing data from the Canadian Early Arthritis Cohort (CATCH), we appliedlatent class analysiswith baseline PROMIS-29 pain, fatigue, depression, anxiety, and sleep scores to select relevant symptoms and levels using AIC, BIC, G-square and log-likelihood results. Baseline PRO and clinical differences among clusters were compared. Next, we evaluated the stability of these clusters at 3 and 6 months.Latent transition analysiswas used to estimate the probability of transitioning among classes.ResultsThe sample included 310 adults with a new RA diagnosis, with 6-month PROs available, and who were MTX naïve at baseline. Participants had a mean age 56, CDAI 29.3, and symptoms for 5 months; 67% were women and 78% White. The optimal symptom set included pain, fatigue, depression, and anxiety (levels: none, mild, moderate, severe). We identified 4 clusters:Minimal(12%);Moderate Pain Dominant(40%);Multiple Moderate-Severe(35%); andMultiple Mild(11%). Clusters had similar sociodemographics exceptMinimalwere slightly older and less female; SJC and TJC were similar among classesMultiple MildorModerate-Severeclasses had significantly worse mood and sleep (Table 1). More patients inMultiple Moderate-SevereandModerate Painhad parenteral steroids whereas numerically more inMinimalorMultiple Mildgroups were on oral steroids. RA Participant Characteristics around diagnosis by symptom clusters.Table 1.Baseline Values(mean SD, N %)MinimalN=38 (12%)Moderate PainN=124 (40%)Multiple Moderate-Severe N=114 (37%)Multiple MildN=34 (11%)SIGPatient Global (0-10)2.6 (2.4)4.8 (2.3)6.9 (2.0)3.9 (2.2)<0.0001PROMIS-29 Anxiety>551 (3%)15 (12%)108 (95%)28 (82%)<0.0001 Depression>550 (0%)14 (11%)100 (88%)22 (65%)<0.0001 Fatigue>553 (8%)49 (40%)106 (93%)12 (35%)<0.0001 Pain Interference>550 (0%)124 (100%)113 (99%)25 (74%)<0.0001 Physical Function<459 (24%)107 (86%)111 (97%)25 (74%)<0.0001 Participation<455 (13%)81 (65%)108 (95%)17 (50%)<0.0001 Sleep>552 (5%)46 (37%)88 (77%)17 (50%)<0.0001Physical Function (0-10)2.9 (2.3)6.1 (2.4)7.7 (1.9)4.2 (2.7)<0.0001Stiffness (0-10)3.2 (2.4)6.3 (2.4)7.7 (1.8)4.3 (2.3)<0.0001Oral steroids16 (42%)40 (32%)29 (25%)14 (41%)0.1470Parenteral steroids8 (21%)44 (35%)62 (54%)7 (21%)<0.0001TJC-28, median (IQR)8 (6,12)9 (5,13)9 (5,13)7 (5,12)0.4626SJC-28, median (IQR)7 (5,12)8 (4,12)7 (4,12)6 (3,11)0.4396CDAI, mean (SD)25.5 (11.4)29.2 (12.7)32.0 (14.0)24.8 (12.6)0.0103Substantial improvement was evident in 67% at 3 months (42%Minimal,25%Multiple Mild;Figure 1). At 6 months, 45% wereMinimaland 25%Multiple Mild. The best prognosis was forMinimal; almost all stayedMinimalat 3 (95%) and 6 (87%) months. Next best wasModerate Painwhere 71% improved (Minimal64%;Multiple Mild7%). A poorer prognosis was seen forMultiple Moderate-Severe: at 3 months, 61% improved (13%Minimal, 33%Multiple Mild).Multiple Mildalso were less likely to improve with 11%Minimaland 6% worsening by 3 months.Figure 1.ConclusionIn this large early RA cohort, we identified 4 distinct symptom clusters around diagnosis that were stable over 6 months and had distinct PRO profiles. At baseline, most (70%) participants were classified asModerate PainDominantorMultiple Moderate Symptoms; the remainder hadminimalormultiple mild symptoms. By examining symptom clusters, we found more homogeneous groups of patients. Our results also suggested that having multiple symptoms around diagnosis was associated with less improvement over the first 6 months, and may signal a more guarded prognosis for symptom improvement and HRQL in early RA.AcknowledgementsCATCH was designed and implemented by the investigators and financially supported through unrestricted research grants from: Amgen and Pfizer Canada since 2007; AbbVie Canada since 2011; Medexus since 2013; Sandoz Canada since 2019; Fresenius Kabi Canada since 2021; Organon Canada since 2021.Previous funding from Hoffman La Roche (2011-21); Sanofi Genzyme (2016-7); Eli Lilly Canada (2016-20); Merck Canada (2017-21) and; Gilead Sciences Canada (2020-21).Disclosure of InterestsSusan J. Bartlett Speakers bureau: Amgen, Janssen, Organon, Merck, Pfizer, Sandoz, Consultant of: Janssen, Merck, Organon, Sandoz, Clifton O Bingham: None declared, Orit Schieir: None declared, Marie-France Valois: None declared, Gilles Boire Speakers bureau: Merck, BMS, Pfizer, Janssen, Consultant of: Amgen, BMS, Celgene, Eli Lilly, Pfizer, Grant/research support from: Amgen, Abbvie, BMS, Eli Lilly, Merck, Novartis, Pfizer, Sandoz, Janet Pope Speakers bureau: UCB, Sandoz, Consultant of: AbbVie, Actelion, Amgen, Bayer, BMS, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Grant/research support from: Abbvie, BMS, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Louis Bessette Speakers bureau: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Consultant of: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Carter Thorne Consultant of: Abbvie, Amgen, Celgene, Centocor, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, Grant/research support from: Abbvie, Celgene, CaREBiodam, Novartis, Pfizer, Diane Tin: None declared, Carol Hitchon Grant/research support from: Pfizer and UCB, Glen Hazlewood: None declared, Edward Keystone Speakers bureau: Amgen, AbbVie, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Pfizer Pharmaceuticals, Sanofi Genzyme, UCB, Consultant of: AbbVie, Amgen, AstraZeneca Pharma, Bristol-Myers Squibb Company, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Genentech Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: AbbVie, Amgen, Gilead Sciences, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, PuraPharm, Sanofi, Vivian Bykerk Consultant of: Amgen, BMS, Gilead, Regeneron, UCB, Grant/research support from: Amgen, BMS, Genzyme, Pfizer, Regeneron Sanofi Aventis, UCB.

Background:Stress is implicated in RA onset and poorer prognoses through changes in neuro-endocrine and autoimmune function. Although many people with RA link disease onset to recent stressful life events, results from retrospective studies are unclear.Objectives:To describe the incidence of major stressors(+STRESS) in year prior to diagnosis and compare characteristics and patient-reported outcomes (PROs) of newly diagnosed RA patients with and without+STRESSat 0 and 12 months.Methods:Data were from early RA patients (symptoms <1 yr) enrolled in the Canadian Early Arthritis Cohort (CATCH) from 2007-17 who met 1987/2010 ACR/EULAR criteria and had ≥12 months of follow-up. Patients reported major psychological (death, divorce/separation, family, financial, other) and physical (motor vehicle accident, surgery, major illness/infection, other) stressors in previous year. We used independent t-tests and chi square to compare characteristics by stressors at baseline, and multivariable regression to examine the impact of+STRESSon disease activity and PROs at 1 year, adjusting for age, sex, education, fibromyalgia, and SJC.Results:The 1933 adults were mostly female (72%), with a mean (SD) age of 55 (15) years. 52% reported 1+ stressors in previous year; family (48%), financial stress (36%), death (35%), surgery (28%), and major illness (26%) were the most common stressors. Patients with +STRESS were more likely to be women, younger, have more comorbidities including fibromyalgia, and higher mean DAS28. Patients with +STRESS also had significantly higher mean pain, fatigue, depression, sleep disturbance, patient global, and HAQ scores at baseline.At 1 year, SJC and the proportion in DAS28 REM was similar between groups. However, PROs (pain, HAQ, Fatigue, Pt Global, Depression, Poor Sleep) remained higher in+STRESS, with evidence of an additive effect for number of stressors and having both physical and psychological stressors (Table). The greatest impacts were on mood, sleep disturbance, and fatigue.Conclusion:In this pan-Canadian early RA cohort, more than half reported 1+ stressful life events in the year prior to diagnosis. Individuals reporting major stressors had significantly worse pain, patient global, disability, depression, fatigue, and sleep disturbance at diagnosis; 1 year later, though disease activity was similar between groups, the effects of +STRESS on PROs persisted. Early RA patients with recent major stressors may benefit from emotional support and stress reduction to optimize how they feel and function.Mean (SD) or N (%)No Stress(N=928; 48%)Physical(N=131; 7%)Psychological(N=658; 34%)Both(N=216; 11%)Age56 (15)56 (15)53 (14)52 (15)Women622 (67%)82 (63%)512 (78%)174 (81%)College Education464 (50%)76 (58%)345 (52%)126 (58%)Rheum Dis Comorbid Index1.1 (1.2)1.4 (1.4)1.1 (1.3)1.4 (1.3)OA or Spinal pain168 (18%)35 (27%)117 (18%)55 (25%)Fibromyalgia diagnosis15 (2%)2 (2%)13 (2%)11 (5%)Symptom duration (months)5.6 (3.0)5.7 (3.0)5.9 (3.0)5.9 (3.0)DAS28 – mean5.0 (1.4)5.1 (1.5)5.0 (1.5)5.2 (1.4)MTX ±csDMARDs679 (73%)100 (76%)489 (74%)166 (77%)Oral Steroids295 (32%)40 (31%)215 (33%)55 (25%)Pain (0-10)5.3 (2.8)5.5 (2.9)5.7 (2.8)6.2 (2.8)HAQ-DI1.0 (0.7)1.2 (0.7)1.1 (0.7)1.3 (0.7)Fatigue (0-10)4.7 (3.1)5.0 (3.0)5.7 (2.9)5.9 (2.9)Patient Global (0-10)5.6 (2.9)6.0 (2.9)6.0 (2.9)6.4 (3.0)Depression (SF12 MCS < 45.6)329 (35%)54 (41%)356 (54%)123 (57%)Poor sleep (0-10)4.5 (3.4)4.8 (3.3)5.3 (3.2)6.0 (3.1)Disclosure of Interests:Nicole Andersen: None declared, Orit Schieir: None declared, Marie-France Valois: None declared, Gilles Boire Grant/research support from: Merck Canada (Registry of biologices, Improvement of comorbidity surveillance)Amgen Canada (CATCH, clinical nurse)Abbvie (CATCH, clinical nurse)Pfizer (CATCH, Registry of biologics, Clinical nurse)Hoffman-LaRoche (CATCH)UCB Canada (CATCH, Clinical nurse)BMS (CATCH, Clinical nurse, Observational Study Protocol IM101664. SEROPOSITIVITY IN A LARGE CANADIAN OBSERVATIONAL COHORT)Janssen (CATCH)Celgene (Clinical nurse)Eli Lilly (Registry of biologics, Clinical nurse), Consultant of: Eli Lilly, Janssen, Novartis, Pfizer, Speakers bureau: Merck, BMS, Pfizer, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Glen Hazlewood: None declared, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi, Carol Hitchon Grant/research support from: UCB Canada; Pfizer Canada, Diane Tin: None declared, Carter Thorne Consultant of: Abbvie, Centocor, Janssen, Lilly, Medexus/Medac, PfizerSpeakers bureau: Medexus/Medac, Edward Keystone Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, Consultant of: AbbVie, Amgen, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Celltrion,Crescendo Bioscience, F. Hoffmann-La Roche Inc, Genentech Inc, Gilead, Janssen Inc, LillyPharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, UCB., Speakers bureau: Amgen, AbbVie, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Pfizer Pharmaceuticals, Sanofi Genzyme, UCB, Vivian Bykerk: None declared, Susan J. Bartlett Consultant of: Pfizer, UCB, Lilly, Novartis, Merck, Janssen, Abbvie, Speakers bureau: Pfizer, UCB, Lilly, Novartis, Merck, Janssen, Abbvie