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Objective Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Methods We use Phage Immunoprecipitation‐Sequencing (PhIP‐Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP‐Seq. We next developed a radio‐labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort. Results PhIP‐Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free–survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD. Conclusion We used PhIP‐Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5‐IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

Background and Aims: Autoimmune hepatitis (AIH) is a severe disease characterized by elevated immunoglobin levels. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain., Methods: Phage Immunoprecipitation-Sequencing (PhIP-seq) was employed to identify autoantibodies in the serum of patients with AIH ( n = 115), compared to patients with other liver diseases (metabolic associated steatotic liver disease (MASH) n = 178, primary biliary cholangitis (PBC), n = 26, or healthy controls, n = 94)., Results: Logistic regression using PhIP-seq enriched peptides as inputs yielded a classification AUC of 0.81, indicating the presence of a predictive humoral immune signature for AIH. Embedded within this signature were disease relevant targets, including SLA/LP, the target of a well-recognized autoantibody in AIH, disco interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). The autoreactive fragment of DIP2A was a 9-amino acid stretch nearly identical to the U27 protein of human herpes virus 6 (HHV-6). Fine mapping of this epitope suggests the HHV-6 U27 sequence is preferentially enriched relative to the corresponding DIP2A sequence. Antibodies against RXFP1, a receptor involved in anti-fibrotic signaling, were also highly specific to AIH. The enriched peptides are within a motif adjacent to the receptor binding domain, required for signaling and serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 singling. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect., Conclusions: These data provide evidence for a novel serological profile in AIH, including a possible functional role for anti-RXFP1, and antibodies that cross react with HHV6 U27 protein., Competing Interests: Declaration of interests statement Dr. DeRisi reports being a consultant for Delve Bio., Inc., Public Health Company Inc., and Allen & Co. Dr Khalili reports receipt of grant funding to her institution from Gilead Sciences Inc and Intercept pharmaceuticals and she serves as a consultant to Gilead Sciences Inc and GlaxoSmithKline Pharmaceuticals.

Objective: Immunocompromised patients with chronic inflammatory disease (CID) may have experienced additional psychosocial burden during the COVID-19 pandemic due to their immunocompromised status. This study was undertaken to determine if vaccination would result in improved patient-reported outcomes longitudinally among individuals with CID undergoing SARS-CoV-2 vaccination regardless of baseline anxiety., Methods: Data are from a cohort of individuals with CID from 2 sites who underwent SARS-CoV-2 vaccination. Participants completed 3 study visits before and after 2 messenger RNA vaccine doses in the initial vaccination series when clinical data were collected. Patient-reported outcomes were measured using the Patient-Reported Outcomes Measurement Information System 29-item Health Profile and expressed as T scores, with 2 groups stratified by high and low baseline anxiety. Mixed-effects models were used to examine longitudinal changes, adjusting for age, sex, and study site., Results: A total of 72% of the cohort was female with a mean ± SD age of 48.1 ± 15.5 years. Overall, sleep disturbance improved following both doses of SARS-CoV-2 vaccinations, and anxiety decreased after the second dose. Physical function scores worsened but did not meet the minimally important difference threshold. When stratifying by baseline anxiety, improvement in anxiety, fatigue, and social participation were greater in the high anxiety group. Physical function worsened slightly in both groups, and sleep disturbance improved significantly in the high anxiety group., Conclusion: Sleep disturbance decreased in a significant and meaningful way in patients with CID upon vaccination. In patients with higher baseline anxiety, social participation increased, and anxiety, fatigue, and sleep disturbance decreased. Overall, results suggest that SARS-CoV-2 vaccination may improve mental health and well-being, particularly among those with greater anxiety., (© 2022 American College of Rheumatology.)

Objective: Systemic sclerosis (SSc) patients are classified according to degree of skin fibrosis (limited and diffuse cutaneous [lc and dc]) and serum autoantibodies. We undertook the present multicenter study to determine whether intrinsic subset (IS) classification based upon skin gene expression yields additional valuable clinical information., Methods: SSc patients and healthy participants (HPs) were classified into Normal-like, Limited, Fibroproliferative, and Inflammatory ISs using a previously trained classifier. Clinical data were obtained (serum autoantibodies, pulmonary function testing, modified Rodnan skin thickness scores [mRSS], and high-resolution chest computed tomography [HRCT]). Statistical analyses were performed to compare patients classified by IS, traditional cutaneous classification, and serum autoantibodies., Results: A total of 223 participants (165 SSc [115 dcSSc and 50 lcSSc] and 58 HPs) were classified. Inflammatory IS patients had higher mRSS (22.1 ± 9.9; P < 0.001) than other ISs and dcSSc patients (19.4 ± 9.4; P = 0.05) despite similar disease duration (median [interquartile range] months 14.9 [19.9] vs. 18.4 [31.6]; P = 0.48). In multivariable modeling, no significant association between mRSS and RNA polymerase III (P = 0.07) or anti-topoisomerase I (Scl-70) (P = 0.09) was found. Radiographic interstitial lung disease (ILD) was more prevalent in Fibroproliferative IS compared with other ISs (91%; P = 0.04) with similar prevalence between lcSSc and dcSSc (67% vs. 76%; P = 0.73). Positive Scl-70 antibody was the strongest ILD predictor (P < 0.001). Interestingly, all lcSSc/Fibroproliferative patients demonstrated radiographic ILD., Conclusions: Classification by IS identifies patients with distinct clinical phenotypes versus traditional cutaneous or autoantibody classification. IS classification identifies subgroups of SSc patients with more radiographic ILD (Fibroproliferative), higher mRSS (Inflammatory), and milder phenotype (Normal-like) and may provide additional clinically useful information to current SSc classification systems., (© 2022 American College of Rheumatology.)

Objective: Lateral flow assays (LFA) are sensitive for detecting antibodies to SARS-CoV-2 proteins within weeks after infection. This study tested samples from immunocompetent adults, and those receiving treatments for chronic inflammatory diseases (CID), before and after mRNA SARS-CoV-2 vaccination., Methods: We compared results obtained with the COVIBLOCK Covid-19 LFA to those obtained by anti-spike (S) ELISA., Results: The LFA detected anti-S antibodies in 29 of 29 (100%) of the immunocompetent and 110 of 126 (87.3%) of the CID participants after vaccination. Semiquantitative LFA scores were statistically significantly lower in samples from immunosuppressed participants, and were significantly correlated with anti-S antibody levels measured by ELISA., Conclusions: This simple LFA test is a practical alternative to laboratory-based assays for detecting anti-S antibodies after infection or vaccination. This type of test may be most useful for testing people in outpatient or resource-limited settings., Competing Interests: MAP receives research support from Lilly paid to the institution and received consultant fees from AbbVie, JK Market Research, and Priovant Therapeutics. PD: Consultant or on an advisory board for Janssen, Pfizer, Prometheus Biosciences, Boehringer Ingelheim, AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, CorEvitas LLC and Scipher Medicine Corporation. He has also received funding under a sponsored research agreement unrelated to the data in the paper from Takeda Pharmaceutical, Arena Pharmaceuticals, Bristol Myers Squibb-Celgene, and Boehringer Ingelheim. SPJW has filed a patent with Washington University for VSV-SARS-CoV-2 mutants to characterize antibody panels (PCT/Us2021/027275). SPJW has received unrelated funding support in sponsored research agreements with Vir Biotechnology., (© 2023 The Authors.)

Background: Longitudinal clerkships provide students with meaningful clinical care roles that promote learning and professional development. It remains unclear how longitudinal primary care clerkships inform students' perceptions of primary care., Objective: To explore perceptions of primary care among medical students enrolled in longitudinal primary care clerkships., Design: Qualitative, semi-structured interviews with medical students over 4 years., Participants: Thirty-eight medical students participated at baseline; 35 participated in a 2-year follow-up interview; 24 participated at 4 years. Each student was enrolled in one of two longitudinal primary care clerkships: a team-based Education-Centered Medical Home (ECMH) or a one-on-one individual preceptorship (IP)., Approach: De-identified interview transcripts were analyzed using a process of open and axial coding, followed by elaborative coding for longitudinal analysis. Codes were compiled into a set of themes and compared across time periods and between clerkships., Key Results: Students reported that primary care serves as a first point of contact, emphasizing longitudinal care with a wide scope of practice and approaching patient care with a biopsychosocial perspective. Student perceptions of primary care greatly expanded over the course of 4 years: for instance, initial perceptions of primary care physicians evolved from "passive gatekeeper" to a more nuanced "quarterback." Students in ECMH, whose clerkship provided more opportunity for patient continuity, further reflected on the relationships they themselves developed with patients., Conclusions: Regardless of their eventual specialty choice, longitudinal experiences may aid all students in fostering a sense of the broad scope and importance of primary care. However, without numerous opportunities to witness continuity of care, students may perceive primary care as having limited scope and importance. Longitudinal clerkships, emphasizing continuity with patients and preceptors, may foster in students a broad and nuanced perspective of the scope of primary care as a field., (© 2021. Society of General Internal Medicine.)

Background: Patients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear., Objective: To determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID., Design: Prospective observational cohort study., Setting: Two U.S. CID referral centers., Participants: Volunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination., Measurements: Anti-SARS-CoV-2 spike (S) IgG + binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination., Results: Most of the 133 participants with CID (88.7%) and all 53 immunocompetent participants developed antibodies in response to mRNA-based SARS-CoV-2 vaccination, although some with CID developed numerically lower titers of anti-S IgG. Anti-S IgG antibody titers after vaccination were lower in participants with CID receiving glucocorticoids ( n  = 17) than in those not receiving them; the geometric mean of anti-S IgG antibodies was 357 (95% CI, 96 to 1324) for participants receiving prednisone versus 2190 (CI, 1598 to 3002) for those not receiving it. Anti-S IgG antibody titers were also lower in those receiving B-cell depletion therapy (BCDT) ( n  = 10). Measures of immunogenicity differed numerically between those who were and those who were not receiving antimetabolites ( n  = 48), tumor necrosis factor inhibitors ( n  = 39), and Janus kinase inhibitors ( n  = 11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies., Limitations: Small sample that lacked demographic diversity, and residual confounding., Conclusion: Compared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study., Primary Funding Source: The Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Background: Chinese residents' practical work experiences are different from those described in Western studies. To explore potential mechanisms underlying the effects of doctor-patient relationships on medical residents' work engagement, verifying a posited mediating effect of role overload, and moderating effect of conflict avoidance, in the Chinese context., Methods: Based on the conservation of resources theory, a composite model was constructed. This study's data were collected from four different Chinese tertiary hospitals; 195 residents undergoing regularization training took this survey. Hierarchical moderated and mediated regression analyses were utilized., Results: Doctor-patient relationship were found to be positively related to residents' work engagement (β=0.31, p≤0.001). Role overload partially mediated the effect of these relationships on work engagement, and the moderating role of conflict avoidance in the relationship between doctor-patient relationship and conflict avoidance was negative., Conclusion: Maintaining good doctor-patient relationship can prompt residents to increase their engagement in work in order to meet their patients' needs. Furthermore, role overload has a particular influence in early career stages. Not only is it necessary for residents to gain a sense of recognition and support while they carry out their job responsibilities, especially while dealing with complex doctor-patient relationship, but it is also important to create work environments that can help residents shape their professional competency., (© 2021. The Author(s).)

Background: Individuals with chronic inflammatory diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management., Methods: We conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG + binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination., Results: Compared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization., Conclusions: CID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder that results in skin fibrosis, autoantibody production, and internal organ dysfunction. We previously identified 4 "intrinsic" subsets of SSc based upon skin gene expression that are found across organ systems. Gene expression regulators that underlie the SSc-intrinsic subsets, or are associated with clinical covariates, have not been systematically characterized. Here, we present a computational framework to calculate the activity scores of gene expression regulators and identify their associations with SSc clinical outcomes. We found that regulator activity scores can reproduce the intrinsic molecular subsets, with distinct sets of regulators identified for inflammatory, fibroproliferative, limited, and normal-like samples. Regulators most highly correlated with modified Rodnan skin score (MRSS) also varied by intrinsic subset. We identified subgroups of patients with fibroproliferative and inflammatory SSc with more severe pathophenotypes, such as higher MRSS and increased likelihood of interstitial lung disease (ILD). Using an independent cohort, we show that the group with more severe ILD was more likely to show forced vital capacity decline over a period of 36-54 months. Our results demonstrate an association among the activation of regulators, gene expression subsets, and clinical variables that can identify patients with SSc with more severe disease.