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Lillian Barra,1 Patrick Liang,2 Susanne M Benseler,3 David A Cabral,4 Aurore Fifi-Mah,5 Yueyang Li,1 Nataliya Milman,6 Marinka Twilt,3 Elaine Yacyshyn,7 Christian Pagnoux8 1Division of Rheumatology, The University of Western Ontario, St Joseph’s Health Care, London, Ontario, 2Division of Rheumatology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, 3Division of Rheumatology, Department of Paediatrics, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, 4Division of Rheumatology, BC Children’s Hospital, Vancouver, British Columbia, 5Division of Rheumatology, South Health Campus, University of Calgary, Calgary, Alberta, 6Division of Rheumatology, Department of Medicine, University of Ottawa, Ottawa, 7Division of Rheumatology, University of Alberta, Edmonton, Alberta, 8Department of Rheumatology, Mount Sinai Hospital, Toronto, University of Toronto, Ontario, Canada Objective: Takayasu arteritis (TAK) is a large vessel vasculitis that predominately affects young women and can cause severe ischemic complications. Given the rarity of TAK, the management of this condition is challenging. We aim to describe current rheumatologist practices for the management of TAK and identify discrepancies and gaps in knowledge. Methods: An online survey (developed by the Canadian Vasculitis Network and approved by the Canadian Rheumatology Association) containing 48 questions with regard to the diagnosis, monitoring and treatment of TAK was distributed to 495 Canadian adult and pediatric rheumatologists by email. Results: Sixty-six rheumatologists completed the survey (13% response rate): the majority (73%) were from academic centers and ≤25% reported managing more than ten patients in their career. For establishing the diagnosis of TAK, they relied on a combination of signs and symptoms of ischemia, elevations of inflammatory markers and vascular imaging (typically computed tomography and magnetic resonance angiography). The frequency of monitoring for disease activity and the methods employed (clinical, laboratory or imaging) were variable. All physicians used corticosteroids for the treatment of TAK, but 42% would treat for at least 6–12 months, 26% for 12–24 months and 23% would never stop corticosteroids. Fifty-three percent would always use an immunosuppressant (most commonly methotrexate or azathioprine) in addition to corticosteroids and the remainder would only start an immunosuppressant in patients with refractory or relapsing disease. Conclusion: Physician practices for the management of TAK are variable, suggesting that there are knowledge gaps, which may impact outcomes in patients with TAK. Keywords: Takayasu arteritis, physician practice patterns, practice guidelines, large vessel vasculitis, aortitis

Background: Behçet disease (BD) is a type of vasculitis with relapsing episodes and multisystemic clinical features, associated with significant morbidity and impact on patients' lives. People affected by BD often participate in discussions of their illness experiences. In-person support groups have limited physical accessibility and a relative lack of anonymity; however, online communities have become increasingly popular., Objective: This study investigates the perspectives and experiences of people affected by BD by examining the content shared and discussed on a subforum of the website Reddit-a popular online space for anonymous discussions., Methods: All discussion threads posted between March 9, 2021, and March 12, 2022, including posts and comments, were examined from the subforum "r/Behcets," an anonymous online community of 1100 members as of March 2022. A Grounded Theory analysis was completed to identify themes and subthemes, and notable quotes were extracted from the threads. Parameters extracted from each post included the number of comments, net upvotes, category, and subcategories. Two research team members read the posts separately to identify initial codes and themes to ensure data saturation was achieved., Results: Six recurring themes were identified: (1) finding connectedness and perspectives through shared experiences, (2) struggles of the diagnostic odyssey, (3) sharing or inquiring about symptoms, (4) expressing strong emotions relating to the experience of BD, (5) the impact of BD on quality of life and personal relationships, as well as (6) COVID-19 and the COVID-19 vaccination in relation to BD. Subthemes within each theme were also identified and explored., Conclusions: This novel study provides a qualitative exploration of the perspectives and experiences of people affected by BD, shared in the anonymous and accessible online community of Reddit. The study found that people impacted by an illness seek to connect and receive validation through shared conditions and experiences. By examining the content shared in r/Behcets, this study highlights the needs of people affected by BD, identifying gaps and areas for improvement in the in-person support they receive., (©Jenny Xiaoyu Li, Elaine Yacyshyn. Originally published in JMIR Formative Research (https://formative.jmir.org), 12.12.2023.)

Objective: To identify the factors that impact COVID-19 vaccine decision-making in vaccine-hesitant vasculitis patients, and compare their perceptions with other rheumatology patients, given existence of data suggesting rheumatology patients may have disease-specific factors that influence their COVID-19 vaccine decision-making., Methods: This cross-sectional study surveyed adult rheumatology patients from the Kaye Edmonton Clinic Rheumatology Clinic, in Canada, between June and August 2021, using an anonymous online questionnaire. Survey responses were analyzed for statistical differences using chi-square analysis., Results: The COVID-19 Vaccine Perceptions Survey had a response rate of 70.9%. Of the total 231 respondents, 103 patients were diagnosed with vasculitis. At the time of the survey, 10.6% of vasculitis patients refused to receive a COVID-19 vaccine compared to 6.3% for other rheumatology patients. Compared to other rheumatology patients, vaccine-hesitant vasculitis patients were significantly more concerned about almost every aspect of available COVID-19 vaccines [e.g., safety ( p < 0.001), components ( p < 0.001)], and feared that they could contract SARS-CoV-2 from a vaccine ( p < 0.001). These vaccine-hesitant patients were also significantly less pleased with the government's pandemic response, less confident in healthcare team-provided information ( p < 0.001), and more likely to report that healthcare providers had no role in their COVID-19 vaccine decision-making ( p < 0.001)., Conclusion: Vaccine-hesitant vasculitis patients may have multiple considerations influencing COVID-19 vaccine hesitancy, including vaccine and disease-specific concerns, along with unfavorable perceptions of the healthcare system (government and healthcare providers). Healthcare providers can address some of these concerns by initiating patient-centered discussions around immunizations to help support educated decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Butt, van Eeden, Kovacs Burns, Saxinger, Clifford, Redmond, Cohen Tervaert and Yacyshyn.)

Myasthenia Gravis (MG) is an autoimmune disease associated with severe neuromuscular weakness. Diagnostic confirmation of MG is typically delayed and secured in about 85% and 50% of patients with generalized and ocular MG, respectively with serum antibodies. We have identified a sensitive and specific diagnostic biomarker for various MG serotypes with quantitative proteomics. Serum proteomes of 18 individuals (MG patients, healthy controls (HC), Rheumatoid Arthritis (RA) were quantified in a pilot study and occurrence of high residual fibrinogen was validated by immunoblotting and further investigated by targeted mass spectrometry on the sera of 79 individuals (31 MG of various serotypes, 30 HC, 18 RA). Initial proteomic analysis identified high residual fibrinogen in MG patient sera which was then validated by antibody-based testing. Subsequently, a blinded study of independent samples showed 100% differentiation of MG patients from controls. A final serological quantification of 14 surrogate peptides derived from α-, β-, and γ-subunits of fibrinogen in 79 individuals revealed fibrinogen to be highly specific and 100% sensitive for MG (p < 0.00001), with a remarkable average higher abundance of > 1000-fold over control groups. Our unanticipated discovery of high levels of residual serum fibrinogen in all MG patients can secure rapid bedside diagnosis of MG., (© 2023. The Author(s).)

Objective: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence., Methods: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation., Results: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering., Conclusion: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Persistent fatigue is a common complaint in ANCA-vasculitis (AAV) patients and has a profound impact on patient's quality of life. The symptoms associated with this fatigue mirror those found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Etiologic and pathophysiologic differences exist between PR3- and MPO-ANCA disease, yet differences in their fatigue manifestations have not been well researched. We compared fatigue and its associations in healthy controls, AAV patients and fibromyalgia controls., Methods: The Canadian consensus criteria were used for ME/CFS diagnosis, and American College of Rheumatology criteria for fibromyalgia diagnosis. Factors such as cognitive failure, depression, anxiety, and sleep disturbances were assessed by patient reported questionnaires. Clinical factors such as BVAS, vasculitis damage index, CRP and BMI were also collected., Findings: Our AAV cohort comprised 52 patients, with a mean age of 44.7 (20-79), 57% (30/52) of the patients were female. We found 51.9% (27/52) of patients fulfilled the diagnostic criteria for ME/CFS, with 37% (10/27) of those having comorbid fibromyalgia. Rates of fatigue were higher in MPO-ANCA patients, than in PR3-ANCA patients, and their symptoms were more similar to the fibromyalgia controls. Fatigue in PR3-ANCA patients was related to inflammatory markers. These differences may be due to the varied pathophysiology of the PR3- and MPO-ANCA serotypes., Interpretation: A large proportion of AAV patients suffer from debilitating fatigue consequential enough to meet the diagnostic criteria for ME/CFS. Fatigue associations were not the same between PR3- and MPO-ANCA patients, suggesting that the underlying mechanisms may be different. Future studies should consider ANCA serotype, as further research may inform different clinical treatment strategies for AAV patients suffering from ME/CFS., Funding: This manuscript was funded by the Dutch Kidney Foundation (17PhD01)., Competing Interests: This manuscript was funded by the Dutch Kidney Foundation (17PhD01). JWCT and MO's research is supported by unrestricted grants from the 10.13039/501100000190University of Alberta (Canada), 10.13039/501100002997Dutch Kidney Foundation, the 10.13039/501100018911University Hospital Foundation and Kaye Grants, Scleroderma Canada, and 10.13039/100001003Boehringer Ingelheim. Additionally, MO is funded by the 10.13039/501100000142Arthritis Society (STAR/IMHA career development award 00049) and Scleroderma Canada. JWCT received speaker honoraria Pfizer and Medexus. JWCT on IDMC of InflaRx until 2021, Chair of IDMC for complement inhibitor. MO received speaker honoraria from Boehringer Ingelheim., (© 2023 The Author(s).)

Introduction/objectives: Some rheumatology patients use or contemplate using cannabis, however, may not be transparent about use with their providers. The objective of this qualitative descriptive study was to describe beliefs, perceptions, and learning needs of adults with rheumatic conditions regarding the use of cannabis products., Methods: Purposive sampling was conducted through a rheumatology clinic and sought participants who were using or thinking about using cannabis. Two online focus groups based on cannabis use patterns (non-users and users) were conducted separately. Interviews were audio recorded and transcribed. Three research team members read the transcripts independently to identify initial codes and themes. Data saturation was reached with the interviews., Results: We recruited 12 participants between 52 and 85 years old. The first theme was pain and desperation. Stigma was the second theme with a perception of physician opposition to cannabis, and the reluctance of many participants to discuss cannabis use with physicians. The final theme was a need for information and a general lack of trustworthy and credible sources. Users were willing to try cannabis even if they still had questions., Conclusion: Rheumatology patients are open to using cannabis due to the burden and suffering associated with pain. They remain silent on the topic, however, because of stigma and lack of engagement from health care professionals, particularly physicians. Patients voiced a strong need for information regarding cannabis and want healthcare providers to initiate discussion. These findings are clinically relevant to the management of rheumatic conditions and the promotion of therapeutic relationships.

Background/objective: The most significant adverse events following SARS-CoV-2 vaccination are myocarditis and pericarditis. Myositis and dermatomyositis have been reported following SARS-CoV-2 infection, but vaccine-induced dermatomyositis (DM) has not been reported. Our case series aimed to characterize new onset dermatomyositis or disease-related flares following SARS-CoV-2 vaccination., Materials and Methods: A total of 53 patients from our institution with a new or pre-existing diagnosis of DM were recruited and consented. Phone interviews were conducted to obtain vaccination status and symptoms following vaccination. Electronic medical records were reviewed to extract age, sex, autoantibody profiles, comorbidities, immunomodulatory therapies, creatine kinase (CK) values, and SARS-CoV-2 vaccination dates from the provincial vaccination registry. For patients who reported disease flares, records were reviewed for the onset and nature of symptoms, extent of organ involvement and changes in immunomodulation., Results: On average, patients received 2.62 vaccine doses (range 1-3 doses). A total of 3 of 51 patients (5.88%) experienced dermatomyositis symptoms following vaccination. Two patients were newly diagnosed with dermatomyositis, one requiring hospitalization. Reported symptom onset following vaccination ranged from 1 to 30 days. Of note, all of these patients had normal CK values, even though there was muscle biopsy-confirmed myositis in one patient. Eight patients in the cohort (15.1%) had asymptomatic CK elevation (<1.5 X ULN)., Conclusion: New onset dermatomyositis or flare up of pre-existing dermatomyositis may be a rare complication in SARS-CoV-2 vaccination although no studies can support a true correlation. Several pathophysiologic mechanisms are proposed., Competing Interests: Author GF received fees from Boehringer Ingelheim, AstraZeneca, and Roche for lectures/advisory boards. Author MO received funding from Boehringer Ingelheim and Mallinckrodt Pharmaceuticals for advisory boards. Author RG reports carrying out clinical trials for Bausch Health, AbbVie, and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chan, Cohen Tervaert, Redmond, Yacyshyn, Ferrara, Hwang, Osman and Gniadecki.)

Objective: This scoping review aims to characterize the current literature on electronic patient-reported outcome measures (ePROMs) in rheumatology and assess the feasibility and utility of ePROMs and mobile health technology in the management of rheumatic disease., Introduction: Patient-reported outcome measures (PROMs) are commonly used in rheumatology as they are important markers of disease activity and overall function, encourage shared decision-making, and are associated with high rates of patient satisfaction. With the widespread use of mobile devices, there is increasing interest in the use of mobile health technology to collect electronic PROMs (ePROM)., Inclusion Criteria: All primary studies that involve the collection of ePROMs using mobile devices by individuals with a rheumatic disease were included. Articles were excluded if ePROMs were measured during clinic appointments., Methods: A scoping review was performed using Medline, Embase, PsycINFO, and CINAHL with index terms and key words related to "patient-reported outcome measures", "rheumatic diseases", and "mobile health technology"., Results: A total of 462 records were identified after duplicates were removed. Of the 70 studies selected for review, 43% were conference proceedings and 57% were journal articles, with the majority published in 2016 or later. Inflammatory arthritis was the most common rheumatic disease studied. Generic ePROMs were used over three times more often than disease-specific ePROMs. A total of 39 (56%) studies directly evaluated the feasibility of ePROMs in clinical practice, 19 (27%) were clinical trials that used ePROMs as study endpoints, 9 (13%) were focus groups or surveys on smartphone application development, and 3 (4%) did not fit into one defined category., Conclusion: The use of ePROMs in rheumatology is a growing area of research and shows significant utility in clinical practice, particularly in inflammatory arthritis. Further research is needed to better characterize the feasibility of ePROMs in rheumatology and their impact on patient outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background: Evidence points to a clear link between air pollution exposure and several chronic diseases though investigations regarding arthritis are still lacking. Emerging evidence suggests an association between ambient air pollution and rheumatoid arthritis. Household air pollution exposure, conversely, is largely unstudied but may be an important consideration for arthritis, particularly in low- and middle-income countries (LMICs), where cooking and heating activities can generate high indoor air pollutant levels., Methods: We investigated the association of household air pollution (electricity vs. gas; kerosene/paraffin; coal/charcoal; wood; or agriculture/crop/animal dung/shrubs/grass as the main fuel used for cooking) and arthritis in six LMICs (China, Ghana, India, Mexico, the Russian Federation, South Africa) using data from Wave I of the World Health Organization Study on Global AGEing and Adult Health (SAGE) (2007-2010). Multivariable analyses were adjusted for sociodemographic, household and lifestyle characteristics and several comorbidities., Results: The use of gas (aOR = 1.76, 95%CI: 1.40-2.21); coal (aOR = 1.74, 95%CI: 1.22-2.47); wood (aOR = 1.69, 95%CI: 1.30-2.19); or agriculture/crop/animal dung/shrubs/grass: aOR = 1.95 (1.46-2.61) fuels for cooking were strongly associated with an increased odds of arthritis, compared to electricity in cluster and stratified adjusted analyses. Gender (female), age (≥50 years), overweight (25.0 ≤BMI<30.0 kg/m2), obesity (BMI ≥30.0 kg/m2), former and current alcohol consumption, and the comorbidities angina pectoris, diabetes, chronic lung disease, depression and hypertension were also associated with a higher odds of arthritis. Underweight (BMI<18.5 kg/m2) and higher education levels (college/university completed/post-graduate studies) were associated with a lower odds of arthritis., Conclusions: These findings suggest that exposure to household air pollution from cook fuels is associated with an increased odds of arthritis in these regions, which warrants further investigation., Competing Interests: The authors have declared that no competing interests exist.

Objective: To assess the extent to which ANSWER-2, an interactive online patient decision aid, reduces patients' decisional conflict and improves their medication-related knowledge and self-management capacity., Methods: We used a pre-post study design. Eligible participants had a diagnosis of rheumatoid arthritis (RA), had been recommended to start using a biologic agent or small-molecule agent or to switch to a new one, and had internet access. Access to ANSWER-2 was provided immediately after enrollment. Outcome measures included 1) the Decisional Conflict Scale (DCS), 2) the Medication Education Impact Questionnaire (MeiQ), and 3) the Partners in Health Scale (PIHS). A paired t-test was used to assess differences pre- and postintervention., Results: The majority of the 50 participants were women (n = 40), and the mean ± SD age of participants was 49.6 ± 12.2 years. The median disease duration was 5 years (25th, 75th percentile: 2, 10 years). The mean ± SD DCS score was 45.9 ± 25.1 preintervention and 25.1 ± 21.8 postintervention (mean change of -21.2 of 100 [95% confidence interval (95% CI) -28.1, -14.4], P < 0.001). Before using ANSWER-2, 20% of participants had a DCS score of <25, compared to 52% of participants after the intervention. Similar results were observed in the PIHS (mean ± SD 25.3 ± 14.8 preintervention and 20.4 ± 13.0 postintervention; mean change of -3.7 of 88 [95% CI -6.3, -1.0], P = 0.009). Findings from the MeiQ were mixed, with statistically significant differences found only in the self-management subscales., Conclusion: Patients' decisional conflict decreased and perceived self-management capacity improved after using ANSWER-2. Future research comparing the effectiveness of ANSWER-2 with that of educational material on biologic agents will provide further insight into its value in RA management., (© 2017, American College of Rheumatology.)

The Canadian Vasculitis research network (CanVasc) is composed of physicians from different medical specialties, including rheumatology and nephrology and researchers with expertise in vasculitis. One of its aims was to develop recommendations for the diagnosis and management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides in Canada. This executive summary features the 19 recommendations and 17 statements addressing general AAV diagnosis and management, developed by CanVasc group based on a synthesis of existing international guidelines, other published supporting evidence and expert consensus considering the Canadian healthcare context.

Objectives: To study variations in Canadian clinical practice patterns for the management of ANCA-associated vasculitis (AAV) and identify points to consider for the development of national recommendations., Material and Methodology: A 30-item needs assessment questionnaire was sent to all members of the Canadian Vasculitis network (CanVasc), Canadian Rheumatology Association (CRA), Canadian Thoracic Society (CTS) and Canadian Society of Nephrology (CSN). Respondent characteristics, practice patterns, concerns and expectations were analyzed., Results: Among 132 physicians who followed at least 1 vasculitis patient and responded to the survey, 39% stated that they felt confident in their management of AAV. Several variations in practice were observed regarding diagnostic procedure, induction and maintenance treatments and use of biologics; some were due to logistic constraints (difficulties in access to some specific tests, drugs or care; lack of health care coverage for the costs). The top 5 topics for which recommendations are expected involve treatment for remission induction, maintenance, refractory disease, and relapse as well as biologics., Conclusion: Practice variations identified in this needs assessment survey will serve to formulate key questions for the development of CanVasc recommendations.

Background: Giant cell arteritis (GCA) and Takayasu's arteritis (TAA) are large vessel vasculitides (LVV) for which corticosteroids (CS) are the mainstay for treatment. In patients with LVV unable to tolerate CS, biological agents have been used with variable effectiveness., Objective: To systematically review the effectiveness and safety of biological agents in patients with LVV., Methods: We searched 5 electronic databases (inception to October 2012) and conference abstracts with no language restrictions. Two reviewers independently selected studies, extracted data and assessed methodological quality. Our protocol was registered in PROSPERO., Results: We included 25 studies (3 RCTs and 22 case series with ≥2 cases). 95 GCA and 98 TAA patients received biological agents. The RCTs using anti-TNF agents (infliximab, etanercept and adalimumab) did not suggest a benefit in GCA. GCA patients receiving tocilizumab, in case series, achieved remission (19 patients) and reduction of corticosteroid dose (mean difference, -16.55 mg/day (95% CI: -26.24, -6.86)). In case series, 75 patients with refractory TAA treated with infliximab discontinued CS 32% of the time. Remission was variably defined and the studies were clinically heterogeneous which precluded further analysis., Conclusion: This systematic review demonstrated a weak evidence base on which to assess the effectiveness of biological treatment in LVV. Evidence from RCTs suggests that anti-TNF agents are not effective for remission or reduction of CS use. Tocilizumab and infliximab may be effective in the management of LVV and refractory TAA, respectively, although the evidence comes from case series. Future analytical studies are needed to confirm these findings.

Objective: To assess the extent to which an online patient decision aid reduced decisional conflict and improved self-management knowledge/skills in patients who were considering methotrexate for rheumatoid arthritis (RA)., Methods: We used a mixed-methods pre-post study design. Eligible participants had a diagnosis of RA, had been prescribed methotrexate but were unsure about starting it, and had access to the internet. Outcome included the Decisional Conflict Scale, the Methotrexate in RA Knowledge Test, and the Effective Consumer Scale. Paired t-tests were used to assess changes before and after the intervention. Randomly selected participants were interviewed at the end of the study about their experiences with the decision aid., Results: Of 30 participants, 23 were women. Mean ± SD age was 54.9 ± 14.9 years and the median disease duration was 1 year (interquartile range 0.3-5.0 years). Mean ± SD decisional conflict changed from 49.50 ± 23.17 preintervention to 21.83 ± 24.12 postintervention (change -27.67 [95% confidence interval -39.89, -15.44]; P < 0.001). Knowledge of methotrexate improved (mean ± SD 30.62 ± 9.26 preintervention and 41.67 ± 6.81 postintervention; P < 0.001), but there was no change in effective consumer attributes (mean ± SD 68.24 ± 12.46 preintervention and 72.94 ± 12.74 postintervention; P = 0.15). Three themes emerged from interviews of 11 participants: seeking confirmation of one's own knowledge of methotrexate, amplifying reluctance when they encountered information contradicting their own experiences, and clarifying thoughts about the next step during the process., Conclusion: Patients' decisional conflict and knowledge improved after using the patient decision aid. Interview findings further highlighted the power of patients' prior knowledge and experiences with RA on how they approach the information presented in a decision aid., (Copyright © 2014 by the American College of Rheumatology.)

Accumulating evidence indicates that the interdomain B regions of ZAP-70 and Syk play pivotal roles in the coupling of T-cell antigen receptor (TCR) stimulation to the activation of downstream signaling pathways. The interdomain B region of ZAP-70 contains at least three candidate sites of tyrosine phosphorylation. In this report, we identify Tyr319 as a functionally important phosphorylation site in the ZAP-70 interdomain B region. TCR crosslinkage triggered a rapid increase in the phosphorylation of Tyr319 in Jurkat T cells. Although mutation of Tyr319 to Phe had no effect on the tyrosine kinase activity of ZAP-70, the resulting ZAP(Y319-->F) mutant failed to reconstitute TCR-dependent Ca2+ mobilization, Ras activation, CD69 expression and NFAT-dependent transcription in ZAP-70-deficient Jurkat cells. These defects were correlated with reduced tyrosine phosphorylation of phospholipase C (PLC)-gamma1 and the LAT adapter protein in the ZAP(Y319-->F)-expressing cells. On the other hand, ZAP(Y319-->F)-expressing cells displayed normal increases in SLP-76 phosphorylation and ERK activation during TCR stimulation. Phosphorylation of Tyr319 promoted the association of ZAP-70 with the SH2 domains of two key signaling molecules, Lck and PLC-gamma1. These studies suggest that Tyr319 phosphorylation is required for the assembly of a ZAP-70-containing signaling complex that leads to the activation of the PLC-gamma1- and Ras-dependent signaling cascades in antigen-stimulated T cells.