Pathological autoantibody internalisation in myositis.

OBJECTIVES: Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption. METHODS: Confocal immunofluorescence microscopy was employed to localise antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to examine the transcriptomic profiles of 669 samples, including those from patients with myositis, disease controls and healthy controls. Additionally, antibodies from myositis patients were introduced into cultured myoblasts through electroporation, and their transcriptomic profiles were analysed using RNA sequencing. RESULTS: In patients with myositis autoantibodies, antibodies accumulated inside myofibres in the same subcellular compartment as the autoantigen. Bulk RNA sequencing revealed that muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibited transcriptomic patterns consistent with dysfunction of the autoantigen. For instance, in muscle biopsies from patients with anti-PM/Scl autoantibodies recognising components of the nuclear RNA exosome complex, an accumulation of divergent transcripts and long non-coding RNAs was observed; these RNA forms are typically degraded by the nuclear RNA exosome complex. Introducing patient antibodies into cultured muscle cells recapitulated the transcriptomic effects observed in human disease. Further supporting evidence suggested that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets. CONCLUSIONS: This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.

Patterns of Care Following a Positive Fecal Blood Test for Colorectal Cancer: A Mixed Methods Study.

BACKGROUND/OBJECTIVE: Multilevel barriers to colonoscopy after a positive fecal blood test for colorectal cancer (CRC) are well-documented. A less-explored barrier to appropriate follow-up is repeat fecal testing after a positive test. We investigated this phenomenon using mixed methods. DESIGN: This sequential mixed methods study included quantitative data from a large cohort of patients 50-89 years from four healthcare systems with a positive fecal test 2010-2018 and qualitative data from interviews with physicians and patients. MAIN MEASURES: Logistic regression was used to evaluate whether repeat testing was associated with failure to complete subsequent colonoscopy and to identify factors associated with repeat testing. Interviews were coded and analyzed to explore reasons for repeat testing. KEY RESULTS: A total of 316,443 patients had a positive fecal test. Within 1 year, 76.3% received a colonoscopy without repeat fecal testing, 3% repeated testing and then received a colonoscopy, 4.4% repeated testing without colonoscopy, and 16.3% did nothing. Among repeat testers (7.4% of total cohort, N = 23,312), 59% did not receive a colonoscopy within 1 year. In adjusted models, those with an initial positive test followed by a negative second test were significantly less likely to receive colonoscopy than those with two successive positive tests (OR 0.37, 95% CI 0.35-0.40). Older age (65-75 vs. 50-64 years: OR 1.37, 95% CI 1.33-1.41) and higher comorbidity score (≥ 4 vs. 0: OR 1.75, 95% CI 1.67-1.83) were significantly associated with repeat testing compared to those who received colonoscopy without repeat tests. Qualitative interview data revealed reasons underlying repeat testing, including colonoscopy avoidance, bargaining, and disbelief of positive results. CONCLUSIONS: Among patients in this cohort, 7.4% repeated fecal testing after an initial positive test. Of those, over half did not go on to receive a colonoscopy within 1 year. Efforts to improve CRC screening must address repeat fecal testing after a positive test as a barrier to completing colonoscopy.

Nailfold capillaroscopy findings of a multicentric multi-ethnic cohort of patients with idiopathic inflammatory myopathies.

OBJECTIVES: To assess nailfold video capillaroscopic (NVC) abnormalities and their association with clinical features, myositis-specific autoantibodies (MSA), and myositis-associated antibodies (MAA) in a large multi-ethnic cohort of patients with idiopathic inflammatory myopathies (IIM). METHODS: We recruited 155 IIM patients from three centres in Mexico, Spain, and the USA. We evaluated the clinical and laboratory features of the patients and performed semiquantitative and quantitative analyses of the NVC. Each NVC study was defined as having a normal, non-specific, early systemic sclerosis (SSc), active SSc, or late SSc pattern. Twenty-three patients had at least one follow-up NVC when disease control was achieved. Quantitative variables were expressed as medians and interquartile range (IQR) and were compared with the Kruskal-Wallis, the Mann-Whitney U-test, and the Wilcoxon test for paired medians. Associations between qualitative variables were assessed with the χ2 test. RESULTS: Most patients were women (68.3%), Hispanic (73.5%), and had dermatomyositis (DM) (61.2%). Fourteen patients (9%) had a normal NVC. A non-specific abnormality pattern was the most frequent (53.9%), and was associated with joint involvement, interstitial lung disease, Jo1 autoantibodies, anti-synthetase syndrome, and immune-mediated necrotising myopathy. The SSc pattern was observed mostly in DM and overlap myositis and was associated with cutaneous features and anti-TIF-1g autoantibodies. After treatment, there was a decrease in the capillaroscopic score, the capillary diameter, and the number of avascular areas, and an increase in capillary density and bushy capillary number. CONCLUSIONS: NVC abnormalities are related to the diagnosis, clinical features, disease activity, and autoantibodies of patients with IIM.

Characterization of Individuals With Hepatitis B Virus-Related Cirrhosis in a Large Integrated Health Care Organization, 2008-2019.

CONTEXT: Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a risk factor for cirrhosis. The management of HBV-related cirrhosis is challenging, with guidelines recommending treatment initiation and regular monitoring for those affected. OBJECTIVE: Our study characterized Kaiser Permanente Southern California patients with HBV-related cirrhosis and assessed whether they received recommended laboratory testing and imaging monitoring. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: We identified KPSC members aged ≥18 years with CHB (defined by 2, consecutive positive hepatitis B surface antigens ≥6 months apart) from 2008 to 2019. Of these patients, we further identified patients with potential HBV-related cirrhosis through ICD-10 code diagnosis, adjudicated via chart review. MAIN OUTCOME MEASURES: Age, race/ethnicity, laboratory tests (eg, alanine aminotransferase [ALT]), and hepatocellular carcinoma (HCC) screening (based on standard screening recommendations via imaging) were described in those with HBV-related cirrhosis versus those without. RESULTS: Among patients with CHB, we identified 65 patients with HBV-related cirrhosis over ~8 years. Diabetes was the most common comorbidity and was approximately 3 times more prevalent among patients with cirrhosis compared to patients without cirrhosis (21.5% vs. 7.1%). Of the 65 patients with cirrhosis, 72.3% (N = 47) received treatment. Generally, we observed that liver function tests (eg, ALT) were completed frequently in this population, with patients completing a median of 10 (6, 16) tests/year. All patients with cirrhosis had ≥1 ALT completed over the study period, and almost all cirrhotic patients (N = 64; 98.5%) had ≥1 HBV DNA test. However, the proportion of yearly imaging visits completed varied across the study years, between 64.0% in 2012 and 87.5% in 2009; overall, 35% (N = 23) completed annual imaging. CONCLUSIONS: Our findings suggest that among patients with HBV-related cirrhosis, at the patient-level, completed imaging orders for HCC screening were sub-optimal. However, we observed adequate disease management practices through frequent liver function tests, linkage to specialty care, image ordering, and shared EHR between KPSC providers.

Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies.

OBJECTIVES: In dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies. METHODS: Phage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren's syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pittsburgh was also screened for anti-Sp4 autoantibodies. RESULTS: Anti-Sp4 autoantibodies were present in 27 (10.5%) patients with DM and 1 (3.3%) patient with RA but not in other clinical groups. In patients with DM, 96.3% of anti-Sp4 autoantibodies were detected in those with anti-TIF1γ autoantibodies. Among 26 TIF1γ-positive patients with anti-Sp4 autoantibodies, none (0%) had cancer. In contrast, among 35 TIF1γ-positive patients without anti-Sp4 autoantibodies, 5 (14%, p=0.04) had cancer. In the validation cohort, among 15 TIF1γ-positive patients with anti-Sp4 autoantibodies, 2 (13.3%) had cancer. By comparison, among 31 TIF1γ-positive patients without anti-Sp4 autoantibodies, 21 (67.7%, p<0.001) had cancer. CONCLUSIONS: Anti-Sp4 autoantibodies appear to identify a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk.

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.

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis.

OBJECTIVES: Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. METHODS: Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM). RESULTS: Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. CONCLUSIONS: We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Anti-FHL1 autoantibodies in juvenile myositis are associated with anti-Ro52 autoantibodies but not with severe disease features.

OBJECTIVES: Four-and-a-half LIM domains 1 (FHL1) is a muscle-specific protein. Autoantibodies against FHL1 were recently discovered in adults with idiopathic inflammatory myopathies (IIMs) and were found to be associated with clinical features and outcomes indicative of increased disease severity. Anti-FHL1 autoantibodies have not been described in children. Here, the prevalence and clinical features associated with anti-FHL1 autoantibodies were examined in a large North American cohort of juvenile patients with IIM. METHODS: Sera from 338 juvenile IIM patients and 91 juvenile healthy controls were screened for anti-FHL1 autoantibodies by ELISA. Clinical characteristics and HLA alleles of those with and without anti-FHL1 autoantibodies were compared among those with juvenile IIM. RESULTS: Anti-FHL1 autoantibodies were present in 10.9% of juvenile IIM patients and 1.1% of controls. The frequency of anti-FHL1 autoantibodies among clinical and serologic subgroups did not differ. A higher percentage of Asian patients had anti-FHL1 autoantibodies (11% vs 0.7%; P = 0.002). Myositis-associated autoantibodies (MAAs) [odds ratio (OR) 2.09 (CI 1.03, 4.32)], anti-Ro52 autoantibodies specifically [OR 4.17 (CI 1.83, 9.37)] and V-sign rash [OR 2.59 (CI 1.22, 5.40)] were associated with anti-FHL1 autoantibodies. There were no differences in other features or markers of disease severity. No HLA associations with anti-FHL1 autoantibodies in Caucasian myositis patients were identified. CONCLUSION: Anti-FHL1 autoantibodies are present in ∼11% of juvenile IIM patients and commonly co-occur with MAAs, including anti-Ro52 autoantibodies. In contrast to adult IIM, anti-FHL1 autoantibodies in juvenile myositis are associated with V-sign rash but not with other distinctive clinical features or worse outcomes.

Understanding Barriers and Facilitators of Pre-exposure Prophylaxis (PrEP) Among Transgender and Gender Diverse Adults in an Integrated Health Care System.

Transgender and gender diverse individuals face health disparities such as higher HIV prevalence, but limited studies have found low PrEP uptake among these populations. To understand both patient and provider perspectives regarding PrEP care for transgender and gender diverse individuals, we conducted a mixed-methods study at Kaiser Permanente Southern California from September 2020 to October 2021. Transgender and gender diverse adults (N = 396) participated in a web-based survey, and qualitative interviews were subsequently conducted with a subset of survey respondents (N = 32) and healthcare providers (N = 8). Among survey respondents, > 75% were familiar with PrEP, and > 40% reported at least one HIV risk factor, but < 5% had taken PrEP. Interview themes included increasing providers' inclusivity in primary care for transgender and gender diverse patients, and reducing logistical barriers and costs associated with PrEP-related visits. To improve PrEP uptake among transgender and gender diverse individuals, barriers across patient, provider, and health system levels must be addressed.

Persistent upregulation of the ß-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle.

In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD), microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology. We now report that increased expression of the beta 6 class V ß-tubulin (tubb6) contributes to the microtubule changes of mdx muscles. Wild-type muscle fibers overexpressing green fluorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in mdx muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly, mdx-based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion, modulation of a ß-tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological per se but reflect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the mdx mouse, may contribute to the repeated cycles of regeneration and to the pathology of the disease.

The indirect immunofluorescence assay autoantibody profiles of myositis patients without known myositis-specific autoantibodies.

OBJECTIVES: The indirect immunofluorescence assay (IIFA) is used to screen for the presence of autoantibodies. Our objective was to determine the prevalence and clinical features of IIFA positive myositis patients without known myositis-specific autoantibodies (MSA). METHODS: Sera from healthy comparators (HC) and patients with dermatomyositis (DM), inclusion body myositis (IBM), and polymyositis (PM) with no detectable MSA were tested by IIFA on HEp-2 cells. The pattern of positivity was classified according to the International Consensus on Antinuclear Antibody Patterns. The prevalence and frequency of each IIFA pattern were compared between the different groups. RESULTS: Sera from 100 HC, 71 DM, 53 IBM, and 69 PM subjects were included in the study. The IIFA was positive in 35% HC compared to 66% DM (p<0.001), 49% IBM, and 64% (p<0.001) PM sera. Among IIFA positive sera, the staining was moderate or intense in 43% HC compared to 79% DM (p<0.001) but just 54% IBM, and 52% PM sera. IIFA positivity was predominantly nuclear in all groups (all >69%). The most common pattern in myositis patients was fine speckled with no differences between groups. In general, IIFA positive and negative DM patients showed similar clinical features and disease activity. CONCLUSIONS: Half of MSA-negative DM patients have moderate/strong IIFA positivity, predominantly with a fine speckled pattern. In contrast, MSA-negative PM, IBM, and healthy comparators are more often weakly positive for IIFA. These findings suggest that unidentified autoantibodies are more likely to exist in DM patients than in the other myositis groups.

Eosinophils Do Not Drive Acute Muscle Pathology in the mdx Mouse Model of Duchenne Muscular Dystrophy.

Eosinophils are present in muscle lesions associated with Duchenne muscular dystrophy and dystrophin-deficient mdx mice that phenocopy this disorder. Although it has been hypothesized that eosinophils promote characteristic inflammatory muscle damage, this has not been fully examined. In this study, we generated mice with the dystrophin mutation introduced into PHIL, a strain with a transgene that directs lineage-specific eosinophil ablation. We also explored the impact of eosinophil overabundance on dystrophinopathy by introducing the dystrophin mutation into IL-5 transgenic mice. We evaluated the degree of eosinophil infiltration in association with myofiber size distribution, centralized nuclei, serum creatine kinase, and quantitative histopathology scores. Among our findings, eosinophils were prominent in the quadriceps muscles of 4-wk-old male mdx mice but no profound differences were observed in the quantitative measures of muscle damage when comparing mdx versus mdx.PHIL versus mdx.IL5tg mice, despite dramatic differences in eosinophil infiltration (CD45+CD11c-Gr1-MHC class IIloSiglecF+ eosinophils at 1.2 ± 0.34% versus <0.1% versus 20 ± 7.6% of total cells, respectively). Further evaluation revealed elevated levels of eosinophil chemoatttractants eotaxin-1 and RANTES in the muscle tissue of all three dystrophin-deficient strains; eotaxin-1 concentration in muscle correlated inversely with age. Cytokines IL-4 and IL-1R antagonist were also detected in association with eosinophils in muscle. Taken together, our findings challenge the long-held perception of eosinophils as cytotoxic in dystrophin-deficient muscle; we show clearly that eosinophil infiltration is not a driving force behind acute muscle damage in the mdx mouse strain. Ongoing studies will focus on the functional properties of eosinophils in this unique microenvironment.

Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis.

OBJECTIVES: Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM. METHODS: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis. RESULTS: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM. CONCLUSIONS: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.

Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis.

OBJECTIVES: Autoantibodies recognising cytosolic 5'-nucleotidase 1A (NT5C1A) are found in adult patients with myositis and other autoimmune diseases. They are especially prevalent in adults with inclusion body myositis (IBM), in which they are associated with more severe weakness and higher mortality. This study was undertaken to define the prevalence and clinical features associated with anti-NT5C1A autoantibodies in juvenile myositis. METHODS: We screened sera from 380 patients with juvenile myositis, 30 patients with juvenile idiopathic arthritis (JIA) and 92 healthy control children for anti-NT5C1A autoantibodies. Clinical characteristics were compared between patients with myositis with and without anti-NT5C1A autoantibodies. RESULTS: Anti-NT5C1A autoantibodies were present in 102 of 380 (27%) patients with juvenile myositis and in 11 of 92 (12%) healthy control children (P=0.002) and 27% of children with JIA (P=0.05 vs controls). Sera of 83 of 307 (27%) patients with juvenile dermatomyositis and 16 of 46 (35%) patients with juvenile overlap myositis were anti-NT5C1A autoantibody-positive (P<0.01 vs healthy controls for each), but sera of only 3 of 27 (11%) patients with juvenile polymyositis were anti-NT5C1A-positive. Patients with juvenile myositis with and without anti-NT5C1A autoantibodies had similar clinical phenotypes. However, patients with anti-NT5C1A autoantibody-positive myositis had greater pulmonary symptoms at diagnosis (P=0.005), more frequent hospitalisations (P=0.01) and required a larger number of medications (P<0.001). CONCLUSION: Anti-NT5C1A autoantibodies are present in more than one-quarter of children with juvenile myositis and JIA compared with only 12% of healthy children, suggesting they are myositis-associated in children. As in adults with IBM, patients with juvenile myositis with anti-NT5C1A autoantibodies have more severe disease.

Anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase necrotizing myopathy masquerading as a muscular dystrophy in a child.

INTRODUCTION: Immune-mediated necrotizing myopathies (IMNMs) are characterized by progressive weakness, elevated serum creatine kinase levels, and necrotizing myopathic features on muscle biopsy. Presence of highly specific autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR) can aid in recognition and confirmation of IMNMs. METHODS: In this study we describe a boy with HMGCR-positive necrotizing myopathy and highlight the clinical features of the patient. RESULTS: In contrast to most adults, the patient described had a more indolent disease course, reminiscent of a muscular dystrophy. Intravenous immunoglobulin monotherapy resulted in a dramatic clinical response with return to normal strength. CONCLUSIONS: Systematic consideration of IMNMs and testing for relevant autoantibodies in children with suspected but genetically unconfirmed muscular dystrophy may help improve diagnostic accuracy and allow timely treatment with potentially highly effective immunotherapies. Muscle Nerve 56: 175-179, 2017.

Changes in Glomerular Filtration Rate After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Fumarate for Human Immunodeficiency Virus Preexposure Prophylaxis.

Background: Tenofovir alafenamide fumarate (TAF) was promoted as a safer alternative to tenofovir disoproxil fumarate (TDF) for human immunodeficiency virus oral preexposure prophylaxis (PrEP). It is unknown if switching from TDF to TAF translates to improved renal function. We used electronic health record (EHR) data to assess changes in creatinine-estimated glomerular filtration rate (eGFR) after switching from TDF to TAF. Methods: We conducted a retrospective cohort study using EHR data from Kaiser Permanente Southern California. We identified individuals who switched from TDF to TAF between October 2019 and May 2022 and used time-varying propensity score matching to identify controls who were on TDF ("nonswitchers"). We then used Bayesian longitudinal modeling to compare differences in eGFR between switching and nonswitching scenarios. Results: Among 5246 eligible individuals, we included 118 TDF to TAF switchers and 114 nonswitchers. Compared to nonswitchers, switchers had older age of starting TDF but similar body weights at index date. A higher proportion of switchers were White, on Medicare or Medicaid, and had dyslipidemia at index date. Switching to TAF was associated with a higher eGFR compared to staying on TDF in 3-15 months post-switch, but the differences were not statistically significant (eg, month 9 difference: 1.27 [95% credible interval, -1.35 to 3.89]). While most of the estimated changes showed eGFR increase associated with switching, most were <2 eGFR units. Sensitivity analyses to address missingness or nonadherence showed similar results. Conclusions: Switching from TDF to TAF for PrEP was associated with a nonsignificant increase in eGFR. Findings need to be confirmed using larger cohorts.

Clinical Features and Immunogenetic Risk Factors Associated With Additional Autoantibodies in Anti-Transcriptional Intermediary Factor 1γ Juvenile-Onset Dermatomyositis.

OBJECTIVE: Novel autoantibody specificities including anti-CCAR1 were recently discovered in adult patients with anti-transcriptional intermediary factor (TIF1)-positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile-onset DM (JDM) and to determine their associated features. METHODS: Sera from 150 patients with anti-TIF1γ autoantibody-positive JDM in a cross-sectional cohort and 90 juvenile healthy controls were assayed for anti-CCAR1, anti-C1Z1, anti-IMMT, anti-TBL1XR1, and anti-Sp4 autoantibodies. Demographics, myositis autoantibodies, clinical features, medications, outcomes, and HLA-DRB1 and HLA-DQA1 alleles were compared between those with and without these autoantibodies. RESULTS: Any one of the anti-TIF1γ-associated autoantibodies was present in 44 patients (29%) overall, including 25 (17%) with anti-Sp4, 22 (15%) with anti-TBL1XR1, 14 (9%) with anti-CCAR1, 2 (1%) with anti-C1Z1, and 2 (1%) with anti-IMMT autoantibodies. These anti-TIF1γ-associated autoantibodies frequently co-occurred. Patients with any of the anti-TIF1γ-associated autoantibodies had less frequent falling (34% [15] vs. 53% [56], P = 0.032) and lower peak muscle enzymes. None of the patients had cancer. Among White patients, HLA-DRB1*03 was protective against an anti-TIF1γ-associated autoantibody (odds ratio 0.20, 95% confidence interval 0.07-0.52). CONCLUSION: Autoantibodies associated with anti-TIF1γ were found in isolation and in combination among a subset of patients with JDM. Patients with these autoantibodies had less severe muscle disease and were not enriched for HLA-DRB1*03. Additional autoantibodies among patients with positive anti-TIF1γ with JDM likely contribute to the heterogeneity of the anti-TIF1γ serologic subgroup.

Myositis-Associated Autoantibodies in Patients With Juvenile Myositis Are Associated With Refractory Disease and Mortality.

OBJECTIVE: Myositis-associated autoantibodies (MAAs) have been associated with overlap myositis, certain disease manifestations such as interstitial lung disease (ILD), and worse prognosis in the idiopathic inflammatory myopathies. MAAs overall remain largely uncharacterized in patients with juvenile-onset myositis. Moreover, it is unknown whether the number of MAAs is associated with disease severity. METHODS: Patients with juvenile myositis in cross-sectional natural history studies who underwent testing for myositis autoantibodies were included. Demographics, myositis autoantibodies, clinical characteristics, medications received, and outcomes of those with and without MAAs were compared. Multivariable logistic regression was performed to determine whether the number of MAAs detected was associated with severe disease features. RESULTS: Among 551 patients, 36% had an MAA and 13% had more than one MAA. Among those who were MAA positive, there was a higher frequency of overlap myositis (18% vs 5.9%, P < 0.001). MAA positivity was associated with certain clinical features, including Raynaud phenomenon (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.41-4.28) and ILD (OR 3.43, 95% CI 1.75-6.96), as well as a chronic disease course (OR 1.72, 95% CI 1.10-2.72) and mortality (OR 3.76, 95% CI 1.72-8.43). The number of MAAs was also associated with mortality (OR 1.83, 95% CI 1.16-2.86). CONCLUSION: MAAs were prevalent in a large cohort of patients with juvenile myositis. ILD, refractory disease, and mortality were associated with MAA positivity. Prospective studies are needed to determine whether early detection of MAAs may lead to improved outcomes for patients with juvenile myositis.