Prevalence and Risk Factors of Post-Acute Sequela of COVID-19 in Adults with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: Incidence and manifestations of post-acute sequelae of COVID-19 (PASC) are poorly defined among immunosuppressed populations. We reported, phenotyped, and assessed risk factors for PASC in adults with systemic autoimmune diseases. METHODS: Persons ≥18 years with systemic autoimmune diseases were recruited into a national, prospective cohort of SARS-CoV-2 vaccination between 12/2020-4/2021. Serial surveys assessed vaccination status, SARS-CoV-2 infection incidence, and disease flares. Participants reporting SARS-CoV-2 infection received a questionnaire assessing symptom duration, severity, and quality of life (QoL) impact; PASC was defined as ≥1 symptom persisting for >12 weeks. PASC syndromes were mapped via overlapping symptom domains. Characteristics were compared between participants who did versus did not report PASC. RESULTS: Among 1615 participants, 590 (36.5%) reported SARS-CoV-2 infection and were sent PASC surveys, 299 (50.7%) of whom responded >12 weeks following reported infection. Respondents were 1.62% female, 90.2% white, median (IQR) age 48(40-60) years with median (IQR) 3 (2-3) vaccine doses at time of first infection. Common diagnoses included inflammatory arthritis (38.5%) and inflammatory bowel disease (14.4%). 89/299 (29.8%) reported PASC, with the most reported symptom domain being neurological/psychological (83.1%); 84% reported an impact on QoL. Participants with PASC reported lower number of preceding vaccines (median [IQR] 2[2-3] versus 3[2-3]; p<0.001) and more reinfections (16.9% versus 5.7%; p=0.004). CONCLUSION: 29.8% of persons with systemic autoimmune disease in a large real-world cohort reported PASC, often affecting QoL. Preceding vaccination may reduce PASC, whereas multiple infections may increase risk, supporting ongoing booster vaccine campaigns and efforts to limit breakthrough infections.

A protocol for scoping reviews on the role of whole-body and dedicated body-part magnetic resonance imaging for assessment of adult and juvenile idiopathic inflammatory myopathies.

Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.

Brepocitinib, a potent and selective TYK2/JAK1 inhibitor: scientific and clinical rationale for dermatomyositis.

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/ß, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

The Impact of Radiation Therapy in Patients with Systemic Sclerosis and Head and Neck Cancer.

OBJECTIVE: Systemic sclerosis (SSc) is considered a relative, or in some cases, absolute contraindication for radiation therapy for various cancers; however, radiation is the standard of care and the best option for tumor control for locally advanced head and neck (H&N) cancer. We present a case series to document postradiation outcomes in patients with SSc and H&N cancer. METHODS: Patients with SSc and H&N cancer treated with radiation were identified from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center research registries. Through chart review, we identified whether patients developed predetermined acute and late side effects or changes in SSc activity from radiation. We further describe therapies used to prevent and treat radiation-induced fibrosis. RESULTS: Thirteen patients with SSc who received radiation therapy for H&N cancer were included. Five-year survival was 54%. Nine patients (69%) developed local radiation-induced skin thickening, and 7 (54%) developed reduced neck range of motion. Two patients required long-term percutaneous endoscopic gastrostomy use due to radiation therapy complications. No patients required respiratory support related to radiation therapy. Regarding SSc disease activity among the patients with established SSc before radiation therapy, none experienced interstitial lung disease progression in the postradiation period. After radiation, one patient had worsening skin disease outside the radiation field; however, this patient was within the first year of SSc, when progressive skin disease is expected. Treatment strategies to prevent radiation fibrosis included pentoxifylline, amifostine, and vitamin E, while intravenous immunoglobulin (IVIG) was used to treat it. CONCLUSION: Although some patients with SSc who received radiation for H&N cancer developed localized skin thickening and reduced neck range of motion, systemic flares of SSc were uncommon. This observational study provides evidence to support the use of radiation therapy for H&N cancer in patients with SSc when radiation is the best treatment option.

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.

Myositis mimics in scleroderma: A case series of neuromuscular diseases that can co-exist in scleroderma.

We present a case series of four patients with systemic sclerosis and skeletal myopathy. While idiopathic inflammatory myopathies, or myositis, are thought to be the most common type of muscle disease seen in systemic sclerosis, we highlight four cases where unique clinical findings and careful assessment ruled out myositis mimics. Key diagnostic tools that can be helpful for clinicians to diagnose a neuromuscular disease are also detailed in this report.

Current myositis clinical trials and tribulations.

With improved understanding of disease pathogenesis and availability of outcome measures, there has been a remarkable increase in the number of therapeutic clinical trials in idiopathic inflammatory myopathies (myositis) over the last three years reaching as many as five trials per site. These trials share similar design and inclusion/exclusion criteria resulting in a competitive clinical trial landscape in myositis. While these are exciting times for the myositis field, we have a number of concerns about the design and conduct of the myositis trials. These include competitive landscape, lengthy placebo arms, underrepresentation of minority groups among participants, use of patient reported outcome measures with limited/no data on validity in myositis, antiquated disease classification criteria, and unclear performance of the ACR/EULAR Myositis Response Criteria in skin-predominant patients despite inclusion of these patients in trials. In this viewpoint, we further discuss these concerns and offer potential solutions such as including patient perspectives in the trial design and adoption of innovative frameworks.

Idiopathic inflammatory myopathies: current insights and future frontiers.

Idiopathic inflammatory myopathies are a group of autoimmune diseases with a broad spectrum of clinical presentations, primarily characterised by immune-mediated muscle injury. Until recently, there was little insight into the pathogenesis of idiopathic inflammatory myopathies, which challenged the recognition of the breadth of heterogeneity of this group of diseases as well as the development of new therapeutics. However, the landscape of idiopathic inflammatory myopathies is evolving. In the past decade, advances in diagnostic tools have facilitated an enhanced understanding of the underlying disease mechanisms in idiopathic inflammatory myopathies, enabling the expansion of therapeutic trials. The fields of transcriptomics, prot§eomics, and machine learning offer the potential to gain greater insights into the underlying pathophysiology of idiopathic inflammatory myopathies. Harnessing insights gained from these sophisticated tools could contribute to the identification of differences at a molecular level among patients, accelerating the development of targeted, tailored therapies. Bolstered by the validation and standardisation of robust outcome measures, many promising therapies are in clinical trial development. Although challenges remain, there is great optimism in the field due to the progress in innovative diagnostics, outcome measures, and therapeutic approaches. In this Review, we discuss the expanding landscape of idiopathic inflammatory myopathies as the frontier of precision medicine becomes imminent.

Novel Imaging Approaches to Cardiac Manifestations of Systemic Inflammatory Diseases: JACC Scientific Statement.

Derangements in the innate and adaptive immune responses observed in systemic inflammatory syndromes contributes to unique elevated atherosclerotic risk and incident cardiovascular disease. Novel multimodality imaging techniques may improve diagnostic precision for the screening and monitoring of disease activity. The integrated application of these technologies lead to earlier diagnosis and noninvasive monitoring of cardiac involvement in systemic inflammatory diseases that will aid in preclinical studies, enhance patient selection, and provide surrogate endpoints in clinical trials, thereby improving clinical outcomes. We review the common cardiovascular manifestations of immune-mediated systemic inflammatory diseases and address the clinical and investigational role of advanced multimodality cardiac imaging.

Identification of Unique microRNA Profiles in Different Types of Idiopathic Inflammatory Myopathy.

Dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) are four major types of idiopathic inflammatory myopathy (IIM). Muscle biopsies from each type of IIM have unique transcriptomic profiles. MicroRNAs (miRNAs) target messenger RNAs (mRNAs), thereby regulating their expression and modulating transcriptomic profiles. In this study, 18 DM, 12 IMNM, 6 AS, 6 IBM, and 6 histologically normal muscle biopsies underwent miRNA profiling using the NanoString nCounter system. Eleven miRNAs were exclusively differentially expressed in DM compared to controls, seven miRNAs were only differentially expressed in AS, and nine miRNAs were specifically upregulated in IBM. No differentially expressed miRNAs were identified in IMNM. We also analyzed miRNA-mRNA associations to identify putative targets of differentially expressed miRNAs. In DM and AS, these were predominantly related to inflammation and cell cycle progression. Moreover, our analysis showed an association between miR-30a-3p, miR-30e-3p, and miR-199b-5p downregulation in DM and the upregulation of target genes induced by type I interferon. In conclusion, we show that muscle biopsies from DM, AS, and IBM patients have unique miRNA signatures and that these miRNAs might play a role in regulating the expression of genes known to be involved in IIM pathogenesis.

Myopathy in systemic sclerosis.

PURPOSE OF REVIEW: Systemic sclerosis associated myopathy (SSc-AM) is a complex, heterogenous disease that is associated with poor outcomes. SSc-AM lacks a clear definition, and continues to be poorly recognized. The purpose of this review is to provide a contemporary overview of the clinical, serological and pathophysiologic findings in SSc-AM to guide optimal recognition and management of this challenging disease manifestation. RECENT FINDINGS: There have been several advances in diagnostic techniques to facilitate characterization of SSc-AM, including muscle MRI, in which findings were correlated to distinct histopathologic categories of muscle involvement in SSc, histopathologic findings of prominent fibrosis or inflammation on biopsy, and the identification of novel autoantibodies associated with SSc-AM, which may be associated with distinct clinical phenotypes. In one of the largest studies to date, 17% of a well phenotyped SSc cohort were found to have myopathy, which was an independent risk of death, even after adjusting for potential confounders, further highlighting the importance of timely recognistion and management of SSc-AM. SUMMARY: There is increasing recognition of the importance of SSc-AM. Novel diagnostic tools provide the opportunity for more detailed insights into pathophysiologic mechanisms, which may facilitate the development of a rigorous consensus definition of SSc-AM.

Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies.

OBJECTIVES: Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients. METHODS: RNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies. RESULTS: A set of 135 genes, including SCRT1 and MADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei. CONCLUSIONS: Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Clinical pearls and promising therapies in myositis.

INTRODUCTION: Idiopathic inflammatory myopathies (IIMs) represent a diverse group of systemic autoimmune disorders with variable clinical manifestations and disease course. Currently, the challenges of IIMs are multifold, including difficulties in timely diagnosis owing to clinical heterogeneity, limited insights into disease pathogenesis, as well as a restricted number of available therapies. However, advances utilizing myositis-specific autoantibodies have facilitated the definition of subgroups as well as the prediction of clinical phenotypes, disease course, and response to treatment. AREAS COVERED: Herein we provide an overview of the clinical presentations of dermatomyositis, anti-synthetase syndrome, immune-mediated necrotizing myopathy, and inclusion body myositis. We then provide an updated review of available and promising therapies for each of these disease groups. We synthesize current treatment recommendations in the context of case-based construct to facilitate application to patient care. Finally, we provide high-yield, clinical pearls relevant to each of the subgroups that can be incorporated into clinical reasoning. EXPERT OPINION: There are many exciting developments on the horizon for IIM. As insights into pathogenesis evolve, the therapeutic armamentarium is expanding with many novel therapies in development, holding promise for more targeted treatment approaches.

Myocarditis in Patients With Idiopathic Inflammatory Myopathies: Clinical Presentation and Outcomes.

OBJECTIVE: To determine the clinical phenotype and outcomes of patients with idiopathic inflammatory myopathies (IIMs) and myocarditis. METHODS: Using the Johns Hopkins Myositis Center Research Registry, we identified 31 adult patients with IIM-out of a total of 3082 with confirmed or suspected muscle disease-with an encounter code of myocarditis from 2004 to 2021. Of these, 14 adult patients with IIM were adjudicated to have clinical myocarditis. Information about demographics, autoantibodies, and clinical outcomes was retrospectively collected and analyzed. RESULTS: Of 14 patients with IIM with clinical myocarditis, the median age at IIM diagnosis was 49 (IQR 35-56) years, and the median age at myocarditis diagnosis was 54 (IQR 36-61) years. The median duration between IIM diagnosis and myocarditis was 3 (IQR 2-9) years. The majority of patients were female (8/14, 57%) and Black (10/14, 71%). Antisynthetase syndrome was the most common IIM subtype (9/14, 64%). Anti-Jo1 (n = 4) and anti-PL12 (n = 3) were the most frequent autoantibodies. At myocarditis diagnosis, most patients (11/14, 79%) had active myositis, defined as elevated creatine kinase and/or muscle weakness; required hospitalization (13/14, 93%); and had reduced left ventricular ejection fraction (LVEF < 50%; 10/14, 71%). Despite intensification of immunosuppression, the 5-year overall survival rate from IIM diagnosis was 84%, and the 5-year overall survival rate from myocarditis diagnosis was 53%. Systolic dysfunction (LVEF < 40%) at final evaluation was observed in all expired patients (n = 6). CONCLUSION: Clinical presentations of myocarditis in this select cohort of patients with IIM were severe and heterogeneous with poor outcomes despite intensification of immunosuppression, potentially reflecting late detection of myocarditis.

Diagnostic Yield of Computed Tomography for Cancer Detection in a Tertiary Referral Population of Idiopathic Inflammatory Myositis Patients.

OBJECTIVE: To inform guidance for cancer detection in patients with idiopathic inflammatory myopathy (IIM), we evaluated the diagnostic yield of computed tomography (CT) imaging for cancer screening/surveillance within distinct IIM subtypes and myositis-specific autoantibody strata. METHODS: We conducted a single-center, retrospective cohort study in IIM patients. Overall diagnostic yield (number of cancers diagnosed/number of tests performed), percentage of false positives (number of biopsies performed not leading to cancer diagnosis/number of tests performed), and test characteristics were determined on CT of the chest and abdomen/pelvis. RESULTS: Within the first 3 years since IIM symptom onset, a total of 9 of 1,011 (0.9%) chest CT scans and 12 of 657 (1.8%) abdomen/pelvis CT scans detected cancer. Diagnostic yields for both CT of the chest and CT of the abdomen/pelvis were highest in dermatomyositis, specifically anti-transcription intermediary factor 1γ (2.9% and 2.4% for CT of the chest and abdomen/pelvis, respectively). The highest percentage of false positives was in patients with antisynthetase syndrome (ASyS) (4.4%) and immune-mediated necrotizing myopathy (4.4%) on CT of the chest, and ASyS (3.8%) on CT of the abdomen/pelvis. Patients ages <40 years old at IIM onset had both low diagnostic yields (0% and 0.5%) and high false-positive rates (1.9% and 4.4%) for CT of the chest and abdomen/pelvis, respectively. CONCLUSION: In a tertiary referral cohort of IIM patients, CT imaging has a wide range of diagnostic yield and frequency of false positives for contemporaneous cancer. These findings suggest that cancer detection strategies targeted according to IIM subtype, autoantibody positivity, and age may maximize cancer detection while minimizing the harms and costs of over-screening.

Coordinated local RNA overexpression of complement induced by interferon gamma in myositis.

Complement proteins are deposited in the muscles of patients with myositis. However, the local expression and regulation of complement genes within myositis muscle have not been well characterized. In this study, bulk RNA sequencing (RNAseq) analyses of muscle biopsy specimens revealed that complement genes are locally overexpressed and correlate with markers of myositis disease activity, including the expression of interferon-gamma (IFNγ)-induced genes. Single cell and single nuclei RNAseq analyses showed that most local expression of complement genes occurs in macrophages, fibroblasts, and satellite cells, with each cell type expressing different sets of complement genes. Biopsies from immune-mediated necrotizing myopathy patients, who have the lowest levels of IFNγ-induced genes, also had the lowest complement gene expression levels. Furthermore, data from cultured human cells showed that IFNγ upregulates complement expression in macrophages, fibroblasts, and muscle cells. Taken together, our results suggest that in myositis muscle, IFNγ coordinates the local overexpression of complement genes that occurs in several cell types.

Association of Anti-CCAR1 Autoantibodies With Decreased Cancer Risk Relative to the General Population in Patients With Anti-Transcriptional Intermediary Factor 1γ-Positive Dermatomyositis.

OBJECTIVE: To describe the disease specificity, clinical phenotype, and risk of cancer in dermatomyositis (DM) patients with autoantibodies against cell division cycle and apoptosis regulator protein 1 (anti-CCAR1). METHODS: The frequency of anti-CCAR1 autoantibodies was measured by enzyme-linked immunosorbent assay in the serum of DM patients from 2 independent cohorts (Johns Hopkins and Stanford), with patients with several other rheumatic diseases and healthy controls used as comparators. Clinical features and the risk of cancer incidence relative to that in the general population were determined in anti-CCAR1-positive DM patients. RESULTS: Anti-CCAR1 antibodies were significantly associated with anti-transcriptional intermediary factor 1γ (anti-TIF1γ) antibodies present in the serum of patients with DM: 80 (32%) of 252 anti-TIF1γ-positive DM patients versus 14 (8%) of 186 anti-TIF1γ-negative DM patients were positive for anti-CCAR1 antibodies (P < 0.001). Anti-CCAR1 antibodies were not detected in any of the 32 serum samples from healthy controls, and were present at very low frequencies in the sera of patients with other rheumatic diseases: 1 (2.3%) of 44 patients with anti-hydroxymethylglutaryl-coenzyme A reductase-positive necrotizing myopathy, 1 (2.3%) of 44 patients with inclusion body myositis, and 3 (6.5%) of 46 patients with systemic lupus erythematosus were positive for anti-CCAR1 antibodies. Upon examining data on occurrence of cancer from the onset of DM onward, the observed number of cancers diagnosed in anti-TIF-1γ-positive DM patients was significantly greater than expected in both cohorts, with a standardized incidence ratio (SIR) of 3.49 (95% confidence interval [95% CI] 2.39-4.92) in the Johns Hopkins cohort and a SIR of 4.54 (95% CI 3.04-6.52) in the Stanford cohort (each P < 0.001). DM patients who were both anti-TIF1γ positive and anti-CCAR1 positive had lower SIRs for cancer, with a SIR of 1.78 (95% CI 0.77-3.51) (P = 0.172) in the Johns Hopkins cohort and a SIR of 1.61 (95% CI 0.44-4.13) (P = 0.48) in the Stanford cohort. CONCLUSION: Anti-CCAR1 autoantibodies are specific for anti-TIF1γ-positive DM. Their presence in anti-TIF1γ-positive patients attenuates the risk of cancer to a level comparable to that seen in the general population.