Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans.

Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using assay for transposase-accessible chromatin coupled to self-transcribing active regulatory region (ATAC-STARR) sequencing. In addition to thousands of cis changes, we discover an unexpected number (∼10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie ∼37% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans, revealing a substantial role for trans divergence-alone and together with cis changes-in regulatory differences between species.

Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies.

INTRODUCTION: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the "Collating the Voice of People with Autoimmune Diseases" COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. METHODS: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients' lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. CONCLUSION: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.

Diagnosing and characterizing inflammatory myopathies at an Australian tertiary public hospital: Resource utilization and direct healthcare costs.

AIM: To determine the direct health service costs and resource utilization associated with diagnosing and characterizing idiopathic inflammatory myopathies (IIMs), and to assess for limitations and diagnostic delay in current practice. METHODS: A retrospective, single-center cohort analysis of all patients diagnosed with IIMs between January 2012 and December 2021 in a large tertiary public hospital was conducted. Demographics, resource utilization and costs associated with diagnosing IIM and characterizing disease manifestations were identified using the hospital's electronic medical record and Health Intelligence Unit, and the Medicare Benefits Schedule. RESULTS: Thirty-eight IIM patients were identified. IIM subtypes included dermatomyositis (34.2%), inclusion body myositis (18.4%), immune-mediated necrotizing myopathy (18.4%), polymyositis (15.8%), and anti-synthetase syndrome (13.2%). The median time from symptom onset to diagnosis was 212 days (IQR: 118-722), while the median time from hospital presentation to diagnosis was 30 days (8-120). Seventy-six percent of patients required emergent hospitalization during their diagnosis, with a median length of stay of 8 days (4-15). The average total cost of diagnosing IIM was $15 618 AUD (STD: 11331) per patient. Fifty percent of patients underwent both MRI and EMG to identify affected muscles, 10% underwent both pan-CT and PET-CT for malignancy detection, and 5% underwent both open surgical and percutaneous muscle biopsies. Autoimmune serology was unnecessarily repeated in 37% of patients. CONCLUSION: The diagnosis of IIMs requires substantial and costly resource use; however, our study has identified potential limitations in current practice and highlighted the need for streamlined diagnostic algorithms to improve patient outcomes and reduce healthcare-related economic burden.

Impaired health-related quality of life in idiopathic inflammatory myopathies: a cross-sectional analysis from the COVAD-2 e-survey.

Objectives: To investigate health-related quality of life in patients with idiopathic inflammatory myopathies (IIMs) compared with those with non-IIM autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs) and without autoimmune diseases (controls) using Patient-Reported Outcome Measurement Information System (PROMIS) instrument data obtained from the second COVID-19 vaccination in autoimmune disease (COVAD-2) e-survey database. Methods: Demographics, diagnosis, comorbidities, disease activity, treatments and PROMIS instrument data were analysed. Primary outcomes were PROMIS Global Physical Health (GPH) and Global Mental Health (GMH) scores. Factors affecting GPH and GMH scores in IIMs were identified using multivariable regression analysis. Results: We analysed responses from 1582 IIM, 4700 non-IIM AIRD and 545 nrAID patients and 3675 controls gathered through 23 May 2022. The median GPH scores were the lowest in IIM and non-IIM AIRD patients {13 [interquartile range (IQR) 10-15] IIMs vs 13 [11-15] non-IIM AIRDs vs 15 [13-17] nrAIDs vs 17 [15-18] controls, P < 0.001}. The median GMH scores in IIM patients were also significantly lower compared with those without autoimmune diseases [13 (IQR 10-15) IIMs vs 15 (13-17) controls, P < 0.001]. Inclusion body myositis, comorbidities, active disease and glucocorticoid use were the determinants of lower GPH scores, whereas overlap myositis, interstitial lung disease, depression, active disease, lower PROMIS Physical Function 10a and higher PROMIS Fatigue 4a scores were associated with lower GMH scores in IIM patients. Conclusion: Both physical and mental health are significantly impaired in IIM patients, particularly in those with comorbidities and increased fatigue, emphasizing the importance of patient-reported experiences and optimized multidisciplinary care to enhance well-being in people with IIMs.

Breakthrough SARS-CoV-2 infection and disease flares in patients with rheumatoid arthritis: result from COVAD e-survey study.

COVID-19 has been suggested as a possible trigger of disease flares in patients with rheumatoid arthritis (RA). However, factors associated with disease flares remain unknown. This study aimed to identify factors associated with breakthrough infection (BIs) and disease flares in patients with RA following COVID-19. We analysed data from RA patients who participated in the COVID-19 vaccination in autoimmune diseases (COVAD) study. Demographic data, patient-reported outcomes, comorbidities, pharmacologic treatment and details regarding disease flares were extracted from the COVAD database. Factors associated with disease flare-ups were determined by multivariate logistic regression analysis. The analysis comprised 1928 patients with RA who participated in the COVAD study. Younger age, Caucasian ethnicity, comorbidities with obstructive chronic pulmonary disease and asthma were associated with COVID-19 breakthrough infection. Moreover, younger age (odds ratio (OR): 0.98, 95% CI 0.96-0.99, p < 0.001), ethnicity other than Asian, past history of tuberculosis (OR: 3.80, 95% CI 1.12-12.94, p = 0.033), treatment with methotrexate (OR: 2.55, 95% CI: 1.56-4.17, p < 0.001), poor global physical health (OR: 1.07, 95% CI 1.00-1.15, p = 0.044) and mental health (OR: 0.91, 95% CI 0.87-0.95, p < 0.001) were independent factors associated disease flares in patients with RA. Our study highlights the impact of socio-demographic factors, clinical characteristics and mental health on disease flares in patients with RA. These insights may help determine relevant strategies to proactively manage RA patients at risk of flares.

Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

Characteristics and risk factors of COVID-19 breakthrough infections in Idiopathic Inflammatory Myopathies: Results from the COVAD study.

OBJECTIVES: To explore prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIM) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. METHODS: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after 2 vaccine doses. We compared BIs characteristics and severity among IIMs, other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HC). Multivariable Cox regression models assessed the risk factors for BI, severe BI and hospitalisations among IIMs. RESULTS: Among 9449 included response, BIs occurred in 1447 (15.3%) respondents, median age 44 years (IQR 21), 77.4% female, and 182 BIs (12.9%) occurred among 1406 IIMs. Multivariable Cox regression among IIMs showed age as a protective factor for BIs [Hazard Ratio (HR)=0.98, 95%CI = 0.97-0.99], hydroxychloroquine and sulfasalazine use were risk factors (HR = 1.81, 95%CI = 1.24-2.64, and HR = 3.79, 95%CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for severe BI (HR = 3.61, 95%CI = 1.09-11.8). Non-White ethnicity (HR = 2.61, 95%CI = 1.03-6.59) was a risk factor for hospitalisation. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIM = 6.0% vs AIRD = 1.8%, nrAID = 2.2%, and HC = 0.9%), intensive care unit admission (IIM = 2.2% vs AIRD = 0.6%, nrAID, and HC = 0%), advanced treatment with antiviral or monoclonal antibodies (IIM = 34.1% vs AIRD = 25.8%, nrAID = 14.6%, and HC = 12.8%), and had more hospitalisation (IIM = 7.7% vs AIRD = 4.6%, nrAID = 1.1%, and HC = 1.5%). CONCLUSION: Patients with IIMs are susceptible to severe COVID-19 BI. Age and immunosuppressive treatments were related to the risk of BIs.

Proximal weakness and creatine kinase elevation in systemic sclerosis: Clinical correlates, prognosis and functional implications.

OBJECTIVES: To determine the frequency, clinical correlates and implications of clinical evidence of muscle disease in systemic sclerosis (SSc). METHODS: Australian Scleroderma Cohort Study participants with ≥1 creatine kinase (CK) and proximal power assessment were subdivided according to presence of proximal weakness (PW: proximal muscle power<5/5) and CK elevation(≥140IU/L). Participants were assigned to one of four groups: concurrent PW&CK elevation, PW alone, CK elevation alone or neither. Between-group comparisons were made with chi-squared, ANOVA or Kruskal-Wallis tests. Survival analysis was performed using time-varying-covariate Cox regression modelling. Longitudinal data were modelled using multinomial logistic and linear regression. RESULTS: Of 1786 participants, 4 % had concurrent PW&CK elevation, 15 % PW alone, 24 % CK elevation and 57 % neither. Participants with PW&CK elevation displayed a severe, inflammatory SSc phenotype, with more frequent dcSSc(p < 0.01), tendon friction rubs(p < 0.01), synovitis(p < 0.01) and digital ulceration(p = 0.03). Multimorbidity(p < 0.01) and cardiopulmonary disease, including ischaemic heart disease(p < 0.01) and pulmonary arterial hypertension(p < 0.01), were most common in those with PW, with and without CK elevation. Men with anti-Scl70 positivity most frequently had CK elevation alone, without other significant clinical differences. Multivariable modelling demonstrated 3.6-fold increased mortality in those with PW&CK elevation (95 %CI 1.9-6.6, p < 0.01) and 2.1-fold increased mortality in PW alone (95 %CI 1.4-3.0, p < 0.01) compared to those without PW or CK elevation. CK elevation alone conferred better survival (HR 0.7, 95 %CI 0.4-1.1, p = 0.09) compared to those with no PW or CK elevation. PW regardless of CK elevation was associated with impaired physical function, with reduced six-minute-walk-distance (p < 0.01), higher HAQ-DI scores (p < 0.01) and increased patient-reported dyspnoea (p = 0.04). CONCLUSION: Clinical features of myopathy are highly prevalent in SSc, affecting almost half of our study cohort. Detection of PW and elevated CK alone, even without imaging or histopathological identification of SSc-myopathy, identified important clinical associations and are associated with poorer function and overall prognosis.

Content analysis of patient support groups related to myositis on Facebook.

INTRODUCTION: Idiopathic inflammatory myopathies (IIM) are heterogeneous and complex, and routine consultation can be overwhelming for patients, or sometimes so rushed that patients feel unable to discuss their needs and wishes adequately. As a result, online patient support groups (PSGs) on social media platforms like Facebook may help provide them with information they are seeking, and the support of the patient community who are living with this condition. Our goal is to explore the current landscape of PSGs in IIM to discuss the future of such groups and their role in supporting patient-driven self-management of complex connective tissue diseases. METHODS: We investigated factors that influence engagement in publicly accessible support groups on Facebook for patients with myositis. We analysed posts from myositis-related Facebook groups and pages between July 10, 2022, and October 2022. Data were extracted from each post, including presentation format (text, picture, video or mixed media) and content type (news, personal feelings or information). To gauge the post's impact, we measured engagement metrics, such as likes, comments, shares and reactions. RESULTS: Nearly three-quarters of the groups were private. Among the open ones, most posts seem to comprise pictures with text. Notably, engagement levels were higher for multimedia posts, with the exception of comments in groups, where engagement was comparatively lower. In terms of content, the majority of posts fell under the 'personal' category, followed by 'information' and 'news' posts, with information posts in groups receiving the most interactions. Moreover, groups exhibited higher total engagement compared to pages when considering all posts cumulatively. CONCLUSIONS: Our observations indicate that patients with myositis seek information on the condition online, and the multimedia nature of content presentation significantly influences engagement. These digital forums serve as valuable platforms for fostering connections among diverse individuals, providing a perceived safe space for sharing their personal experiences and varied perspectives, and potentially mitigating social isolation. Key Points • Patient support groups on myositis are a key source of support and information for patients. • Public posts with multimedia content garner the most engagement. • The majority of posts are personal in nature, with a smaller proportion of content providing news or information.

Flares in IIMs and the timeline following COVID-19 vaccination: a combined analysis of the COVAD-1 and -2 surveys.

OBJECTIVES: Disease flares in the post-coronavirus disease 2019 (COVID-19) vaccination period represent a prominent concern, though risk factors are poorly understood. We studied these flares among patients with idiopathic inflammatory myopathies (IIMs) and other autoimmune rheumatic diseases (AIRDs). METHODS: The COVAD-1 and -2 global surveys were circulated in early 2021 and 2022, respectively, and we captured demographics, comorbidities, AIRDs details, COVID-19 infection history and vaccination details. Flares of IIMs were defined as (a) patient self-reported, (b) immunosuppression (IS) denoted, (c) clinical sign directed and (d) with >7.9-point minimal clinically significant improvement difference worsening of Patient-Reported Outcomes Measurement Information System (PROMIS) PROMISPF10a score. Risk factors of flares were analysed using regression models. RESULTS: Of 15 165 total respondents, 1278 IIMs (age 63 years, 70.3% female, 80.8% Caucasians) and 3453 AIRDs were included. Flares of IIM were seen in 9.6%, 12.7%, 8.7% and 19.6% patients by definitions (a) to (d), respectively, with a median time to flare of 71.5 (10.7-235) days, similar to AIRDs. Patients with active IIMs pre-vaccination (OR 1.2; 95% CI 1.03, 1.6, P = 0.025) were prone to flares, while those receiving rituximab (OR 0.3; 95% CI 0.1, 0.7, P = 0.010) and AZA (OR 0.3, 95% CI 0.1, 0.8, P = 0.016) were at lower risk. Female gender and comorbidities predisposed to flares requiring changes in IS. Asthma (OR 1.62; 95% CI 1.05, 2.50, P = 0.028) and higher pain visual analogue score (OR 1.19; 95% CI 1.11, 1.27, P < 0.001) were associated with disparity between self-reported and IS-denoted flares. CONCLUSION: A diagnosis of IIMs confers an equal risk of flares in the post-COVID-19 vaccination period to AIRDs, with active disease, female gender and comorbidities conferring a higher risk. Disparity between patient- and physician-reported outcomes represents a future avenue for exploration.

Global disparities in the treatment of idiopathic inflammatory myopathies: results from an international online survey study.

OBJECTIVES: We aimed to explore current practice and interregional differences in the treatment of idiopathic inflammatory myopathies (IIMs). We triangulated these observations considering countries' gross national income (GNI), disease subtypes, and symptoms using patient-reported information. METHODS: A cross-sectional ancillary analysis of the 'COVID-19 vaccination in auto-immune disease' (COVAD) e-survey containing demographic characteristics, IIM subtypes (DM, PM, IBM, anti-synthetase syndrome [ASSD], immune-mediated necrotizing myopathy [IMNM], overlap myopathies [OM]), current symptoms (surrogate for organ involvement) and treatments (corticosteroids [CS], immunomodulators [IM], i.e. antimalarials, immunosuppressants [IS], IVIG, biologic treatments and targeted-synthetic small molecules). Treatments were presented descriptively according to continents, GNI, IIM and organ involvement, and associated factors were analysed using multivariable binary logistic regressions. RESULTS: Of 18 851 respondents from 94 countries, 1418 with IIM were analysed (age 61 years, 62.5% females). DM (32.4%), IBM (24.5%) and OM (15.8%) were the most common subtypes. Treatment categories included IS (49.4%), CS (38.5%), IM (13.8%) and IVIG (9.4%). Notably, treatments varied across regions, GNI categories (IS mostly used in higher-middle income, IM in lower-middle income, IVIG and biologics largely limited to high-income countries), IIM subtypes (IS and CS associated with ASSD, IM with OM and DM, IVIG with IMNM, and biologic treatments with OM and ASSD) and disease manifestations (IS and CS with dyspnoea). Most inter-regional treatment disparities persisted after multivariable analysis. CONCLUSION: We identified marked regional treatment disparities in a global cohort of IIM. These observations highlight the need for international consensus-driven management guidelines considering patient-centred care and available resources.

COVID-19 breakthrough infections in type 1 diabetes mellitus: a cross-sectional study by the COVID-19 Vaccination in Autoimmune Diseases (COVAD) Group.

To investigate the frequency, profile, and severity of COVID-19 breakthrough infections (BI) in patients with type I diabetes mellitus (T1DM) compared to healthy controls (HC) after vaccination. The second COVID-19 Vaccination in Autoimmune Diseases (COVAD-2) survey is a multinational cross-sectional electronic survey which has collected data on patients suffering from various autoimmune diseases including T1DM. We performed a subgroup analysis on this cohort to investigate COVID-19 BI characteristics in patients with T1DM. Logistic regression with propensity score matching analysis was performed. A total of 9595 individuals were included in the analysis, with 100 patients having T1DM. Among the fully vaccinated cohort, 16 (16%) T1DM patients had one BI and 2 (2%) had two BIs. No morbidities or deaths were reported, except for one patient who required hospitalization with oxygen without admission to intensive care. The frequency, clinical features, and severity of BIs were not significantly different between T1DM patients and HCs after adjustment for confounding factors. Our study did not show any statistically significant differences in the frequency, symptoms, duration, or critical care requirements between T1DM and HCs after COVID-19 vaccination. Further research is needed to identify factors associated with inadequate vaccine response in patients with BIs, especially in patients with autoimmune diseases.

Correlates of breakthrough COVID-19 in vaccinated patients with systemic sclerosis: survival analysis from a multicentre international patient-reported survey.

This study aimed to assess the incidence, predictors, and outcomes of breakthrough infection (BI) following coronavirus disease (COVID-19) vaccination in patients with systemic sclerosis (SSc), a risk group associated with an immune-suppressed state and high cardiopulmonary disease burden. Cross-sectional data from fully vaccinated respondents with SSc, non-SSc autoimmune rheumatic diseases (AIRDs), and healthy controls (HCs) were extracted from the COVAD database, an international self-reported online survey. BI was defined according to the Centre for Disease Control definition. Infection-free survival was compared between the groups using Kaplan-Meier curves with log-rank tests. Cox proportional regression was used to assess the association between BI and age, sex, ethnicity, and immunosuppressive drugs at the time of vaccination. The severity of BI in terms of hospitalization and requirement for oxygen supplementation was compared between groups. Of 10,900 respondents, 6836 fulfilled the following inclusion criteria: 427 SSc, 2934 other AIRDs, and 3475 HCs. BI were reported in 6.3% of SSc, 6.9% of non-SSc AIRD, and 16.1% of HCs during a median follow-up of 100 (IQR: 60-137) days. SSc had a lower risk for BI than HC [hazard ratio (HR): 0.56 (95% CI 0.46-0.74)]. BIs were associated with age [HR: 0.98 (0.97-0.98)] but not ethnicity or immunosuppressive drugs at the time of vaccination. Patients with SSc were more likely to have asymptomatic COVID-19, but symptomatic patients reported more breathlessness. Hospitalization [SSc: 4 (14.8%), HCs: 37 (6.6%), non-SSc AIRDs: 32(15.8%)] and the need for oxygenation [SSc: 1 (25%); HC: 17 (45.9%); non-SSc AIRD: 13 (40.6%)] were similar between the groups. The incidence of BI in SSc was lower than that in HCs but comparable to that in non-SSc AIRDs. The severity of BI did not differ between the groups. Advancing age, but not ethnicity or immunosuppressive medication use, was associated with BIs.

Gender differences in patient experience in idiopathic inflammatory myopathies: Sub analysis from the COVAD dataset.

OBJECTIVES: We aimed to investigate gender-based differences in idiopathic inflammatory myopathies (IIMs), with a particular focus on patient-reported outcomes, utilizing data obtained through the international COVID-19 vaccination in autoimmune disease (COVAD) e-survey. METHODS: Patient-reported outcomes including fatigue, pain, and physical function were extracted from the COVAD database and compared between genders, adjusting for demographics and IIM subgroups by multivariable analysis. Inclusion body myositis (IBM) was analysed separately because of substantial differences in outcomes. RESULTS: 1197 complete responses from patients with IIMs as of 31 August 2021 were analysed. Seventy percent were women. Women were younger (58 [48-68] vs. 69 [58-75] years old, median [IQR], p < 0.001) and more likely to suffer from autoimmune multimorbidity, defined as three or more autoimmune diseases in an individual patient (11.4% vs. 2.8%, p < 0.001). In non-IBM IIMs, fatigue visual analogue scale scores were higher in women (5 [3-7] vs. 4 [2-6], median [IQR], p = 0.004), whereas no significant gender-based differences were noted in IBM. Multivariable analysis in non-IBM IIMs revealed women, residence in high-income countries, overlap myositis, and autoimmune multimorbidity were independently associated with increased fatigue. CONCLUSIONS: Women with IIMs suffer from autoimmune multimorbidity and experience increased fatigue compared to men.

Delayed adverse events following COVID-19 vaccination in patients with systemic sclerosis and other autoimmune diseases: a substudy of the COVAD-2 cohort.

Data on short-term safety of COVID-19 vaccination in patients with systemic sclerosis (SSc) were explored previously in the first COVID-19 vaccination in autoimmune diseases (COVAD) survey conducted in 2021. However, delayed adverse events (ADEs) (occurring > 7 days post-vaccination) are poorly characterized in these patients with SSc. In this study, we analysed delayed COVID-19 vaccine-related ADEs among patients with SSc, other systemic autoimmune and inflammatory disorders (SAIDs) and healthy controls (HCs) using data from the second COVAD study conducted in 2022. The COVAD-2 study was a cross-sectional, patient self-reported global e-survey conducted from February to June 2022. Data on demographics, SSc/SAID disease characteristics, COVID-19 infection history, and vaccination details including delayed ADEs as defined by the Centre for Disease Control were captured and analysed. Among 17,612 respondents, 10,041 participants fully vaccinated against COVID-19 were included for analysis. Of these, 2.6% (n = 258) had SSc, 63.7% other SAIDs, and 33.7% were HCs. BNT162b2 Pfizer (69.4%) was the most administered vaccine, followed by MRNA-1273 Moderna (32.25%) and ChadOx1 nCOV-19 Oxford/AstraZeneca (12.4%) vaccines. Among patients with SSc, 18.9% reported minor, while 8.5% experienced major delayed ADEs, and 4.6% reported hospitalization. These frequencies were comparable to those of the ADEs reported by other patients with SAIDs and HCs. However, patients with SSc reported a higher frequency of difficulty in breathing than HCs [OR 2.3 (1.0-5.1), p = 0.042]. Patients with diffuse cutaneous SSc experienced minor ADEs [OR 2.1 (1.1-4.4), p = 0.036] and specifically fatigue more frequently [OR 3.9 (1.3-11.7), p = 0.015] than those with limited cutaneous SSc. Systemic sclerosis patients with concomitant myositis reported myalgia more frequently [OR 3.4 (1.1-10.7), p = 0.035], while those with thyroid disorders were more prone to report a higher frequency of joint pain [OR 5.5 (1.5-20.2), p = 0.009] and dizziness [OR 5.9 (1.3-27.6), p = 0.024] than patients with SSc alone. A diagnosis of SSc did not confer a higher risk of delayed post-COVID-19 vaccine-related ADEs overall compared with other SAIDs and HCs. However, the diffuse cutaneous phenotype and coexisting autoimmune conditions including myositis and thyroid disease may increase the risk of minor ADEs. These patients may benefit from pre-vaccination counselling, close monitoring, and early initiation of appropriate care in the post-COVID-19 vaccination period.

COVID-19 vaccine safety during pregnancy and breastfeeding in women with autoimmune diseases: results from the COVAD study.

OBJECTIVES: We investigated COVID-19 vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. METHODS: Delayed-onset (>7 days) vaccine-related adverse events (AE), disease flares (DF), and AID-related treatment modifications were analyzed upon diagnosis of AID versus healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. RESULTS: Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, p= 0.01; minor AE 40% vs 25.9%, p= 0.03; major AE 17.5% vs 4.6%, p< 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination DF were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a DF were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. CONCLUSION: This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and the fetus by passive immunization appear to outweigh potential risks.

High fatigue scores in patients with idiopathic inflammatory myopathies: a multigroup comparative study from the COVAD e-survey.

Idiopathic inflammatory myopathies (IIMs) confer a significant risk of disability and poor quality of life, though fatigue, an important contributing factor, remains under-reported in these individuals. We aimed to compare and analyze differences in visual analog scale (VAS) scores (0-10 cm) for fatigue (VAS-F) in patients with IIMs, non-IIM systemic autoimmune diseases (SAIDs), and healthy controls (HCs). We performed a cross-sectional analysis of the data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) international patient self-reported e-survey. The COVAD survey was circulated from December 2020 to August 2021, and details including demographics, COVID-19 history, vaccination details, SAID details, global health, and functional status were collected from adult patients having received at least one COVID-19 vaccine dose. Fatigue experienced 1 week prior to survey completion was assessed using a single-item 10 cm VAS. Determinants of fatigue were analyzed in regression models. Six thousand nine hundred and eighty-eight respondents (mean age 43.8 years, 72% female; 55% White) were included in the analysis. The overall VAS-F score was 3 (IQR 1-6). Patients with IIMs had similar fatigue scores (5, IQR 3-7) to non-IIM SAIDs [5 (IQR 2-7)], but higher compared to HCs (2, IQR 1-5; P < 0.001), regardless of disease activity. In adjusted analysis, higher VAS-F scores were seen in females (reference female; coefficient -0.17; 95%CI -0.21 to -13; P < 0.001) and Caucasians (reference Caucasians; coefficient -0.22; 95%CI -0.30 to -0.14; P < 0.001 for Asians and coefficient -0.08; 95%CI -0.13 to 0.30; P = 0.003 for Hispanics) in our cohort. Our study found that patients with IIMs exhibit considerable fatigue, similar to other SAIDs and higher than healthy individuals. Women and Caucasians experience greater fatigue scores, allowing identification of stratified groups for optimized multidisciplinary care and improve outcomes such as quality of life.

Long-term safety of COVID vaccination in individuals with idiopathic inflammatory myopathies: results from the COVAD study.

Limited evidence on long-term COVID-19 vaccine safety in patients with idiopathic inflammatory myopathies (IIMs) continues to contribute to vaccine hesitancy. We studied delayed-onset vaccine adverse events (AEs) in patients with IIMs, other systemic autoimmune and inflammatory disorders (SAIDs), and healthy controls (HCs), using data from the second COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. A validated self-reporting e-survey was circulated by the COVAD study group (157 collaborators, 106 countries) from Feb-June 2022. We collected data on demographics, comorbidities, IIM/SAID details, COVID-19 history, and vaccination details. Delayed-onset (> 7 day) AEs were analyzed using regression models. A total of 15165 respondents undertook the survey, of whom 8759 responses from vaccinated individuals [median age 46 (35-58) years, 74.4% females, 45.4% Caucasians] were analyzed. Of these, 1390 (15.9%) had IIMs, 50.6% other SAIDs, and 33.5% HCs. Among IIMs, 16.3% and 10.2% patients reported minor and major AEs, respectively, and 0.72% (n = 10) required hospitalization. Notably patients with IIMs experienced fewer minor AEs than other SAIDs, though rashes were expectedly more than HCs [OR 4.0; 95% CI 2.2-7.0, p < 0.001]. IIM patients with active disease, overlap myositis, autoimmune comorbidities, and ChadOx1 nCOV-19 (Oxford/AstraZeneca) recipients reported AEs more often, while those with inclusion body myositis, and BNT162b2 (Pfizer) recipients reported fewer AEs. Vaccination is reassuringly safe in individuals with IIMs, with AEs, hospitalizations comparable to SAIDs, and largely limited to those with autoimmune multimorbidity and active disease. These observations may inform guidelines to identify high-risk patients warranting close monitoring in the post-vaccination period.

Cardiovascular manifestations in idiopathic inflammatory myopathies.

Cardiovascular involvement in idiopathic inflammatory myopathies (IIM) is an understudied area which is gaining increasing recognition in recent times. Recent advances in imaging modalities and biomarkers have allowed the detection of subclinical cardiovascular manifestations in IIM. However, despite the availability of these tools, the diagnostic challenges and underestimated prevalence of cardiovascular involvement in these patients remain significant. Notably, cardiovascular involvement remains one of the leading causes of mortality in patients with IIM. In this narrative literature review, we outline the prevalence and characteristics of cardiovascular involvement in IIM. Additionally, we explore investigational modalities for early detection of cardiovascular involvement, as well as newer approaches in screening to facilitate timely management. Key points • Cardiac involvement in IIM in majority cases is subclinical and a major cause of mortality. • Cardiac magnetic resonance imaging is sensitive for detection of subclinical cardiac involvement.