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.

Subclinical myocardial involvement in a cohort of patients with antisynthetase syndrome.

OBJECTIVES: There is an increasing interest in knowing whether patients with antisynthetase syndrome (ASSD) may have silent myocardial interstitial involvement. Mapping techniques in cardiac magnetic resonance (CMR) can detect subclinical myocardial involvement. The purpose of this study was to identify alterations in multiparametric CMR in ASSD patients without overt cardiac involvement. METHODS: Patients diagnosed with ASSD underwent a CMR along with the standard clinical workup, investigation of specific and associated myositis antibodies, and high-resolution chest CT. The CMR protocol includes routine morphologic, functional, and late gadolinium enhancement sequences in standard cardiac planes, as well as native T1 and T2 mapping sequences and extracellular volume (ECV) calculation. RESULTS: Twenty-five patients were included in this study (56% women; median age 56.3 years). Three patients were considered in the acute phase at the time of inclusion. Eight patients (32%) showed pathological findings in CMR (6 stable disease, 2 acute phase). Elevated T1, T2 and ECV mapping values were found in 20% (5/25), 17% (4/25) and 24% (6/25) of the group, respectively. Two patients in the acute phase had increased values of both T2 and ECV. CONCLUSIONS: Subclinical myocardial involvement in ASSD is not rare (32%) although its clinical significance is uncertain. Myocardial oedema (T2) was the most frequent finding, followed by increased T1 and/or ECV values likely signalling interstitial fibrosis. Of note, patients in the acute phase showed elevated T2 values.

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.

COVID-19 Vaccination in Autoimmune Diseases (COVAD) study: Vaccine safety in idiopathic inflammatory myopathies.

INTRODUCTION/AIMS: In this study we investigated COVID-19 vaccination-related adverse events (ADEs) 7 days postvaccination in patients with idiopathic inflammatory myopathies (IIMs) and other systemic autoimmune and inflammatory disorders (SAIDs). METHODS: Seven-day vaccine ADEs were collected in an international patient self-reported e-survey. Descriptive statistics were obtained and multivariable regression was performed. RESULTS: Ten thousand nine hundred respondents were analyzed (1227 IIM cases, 4640 SAID cases, and 5033 healthy controls [HCs]; median age, 42 [interquartile range, 30-455] years; 74% female; 45% Caucasian; 69% completely vaccinated). Major ADEs were reported by 76.3% of the IIM patients and 4.6% reported major ADEs. Patients with active IIMs reported more frequent major (odds ratio [OR], 2.7; interquartile range [IQR], 1.04-7.3) and minor (OR, 1.5; IQR, 1.1-2.2) ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR, 2.3; IQR, 1.2-4.2) than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9; IQR, 1.1-3.3; and OR, 2.2; IQR, 1.1-4.3, respectively). Overall, ADEs were less frequent in inclusion-body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients. DISCUSSION: Seven-day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID-19 through vaccination likely outweighs the risk of vaccine-related ADEs. Our results may inform future guidelines regarding COVID-19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long-term outcomes and disease flares are needed to shed more light on developing future COVID-19 vaccination guidelines.

PET Scan: Nuclear Medicine Imaging in Myositis.

PURPOSE OF REVIEW: Positron emission tomography (PET) combined with computed tomography (CT) has proven useful as a cancer screening technique in patients with inflammatory myopathy, mainly dermatomyositis. In this review, we focus on advances in this direction and other potential applications of PET/CT in patients with inflammatory myopathy. RECENT FINDINGS: Cancer screening by PET/CT seems suitable and cost-effective in patients with myositis. It has also shown value as a hybrid technique for diagnosing myositis versus controls and could be of interest for differentiating between polymyositis and sporadic inclusion body myositis. Quantification of muscle activity by PET/CT seems reliable. Preliminary data suggest that it could also be used to diagnose and measure the activity of the disease in the lung. PET/CT should be in the toolbox of physicians managing patients with myositis. The multiple applications of PET/CT include its value for cancer screening, measuring the activity of the disease in muscle, and helping to differentiate between myositis phenotypes. The possibility to diagnose and monitor inflammatory lung activity remains to be demonstrated in well-designed studies.

Pathogenic autoantibody internalization in myositis.

Objectives: Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins. Methods: Confocal immunofluorescence microscopy was used to localize antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to study the transcriptomic profiles of 668 samples from patients with myositis, disease controls, and healthy controls. Antibodies from myositis patients were introduced into cultured myoblasts by electroporation and the transcriptomic profiles of the treated myoblasts were studied by bulk RNA sequencing. Results: In patients with myositis autoantibodies, antibodies accumulated inside myofibers in the same subcellular compartment as the autoantigen. Each autoantibody was associated with effects consistent with dysfunction of its autoantigen, such as the derepression of genes normally repressed by Mi2/NuRD in patients with anti-Mi2 autoantibodies, the accumulation of RNAs degraded by the nuclear RNA exosome complex in patients with anti-PM/Scl autoantibodies targeting this complex, and the accumulation of lipids within myofibers of anti-HMGCR-positive patients. Internalization of patient immunoglobulin into cultured myoblasts recapitulated the transcriptomic phenotypes observed in human disease, including the derepression of Mi2/NuRD-regulated genes in anti-Mi2-positive dermatomyositis and the increased expression of genes normally degraded by the nuclear RNA exosome complex in anti-PM/Scl-positive myositis. Conclusions: In myositis, autoantibodies are internalized into muscle fibers, disrupt the biological function of their autoantigen, and mediate the pathophysiology of the disease.

Cancer screening in idiopathic inflammatory myopathies: Ten years experience from a single center.

OBJECTIVE: There is a well-recognized association between cancer and myositis, so cancer screening at diagnosis is recommended. We aim to report the results of our cancer screening strategy and to ascertain the reliability of using PET/CT to identify cancer-associated myositis (CAM) in a large cohort of patients with myositis from a single center over 10 years. METHODS: This retrospective observational study included all patients diagnosed with any type of myositis except for inclusion body myositis. Cancer screening strategy was individualized according to clinical and serological data, including PET/CT as the main test to detect occult cancer (OC). Procedures derived from a positive PET/CT were registered. Qualitative data expressed as percentages, and quantitative data as the median with the interquartile range were analyzed. A ROC curve was used to estimate the reliability of PET/CT for CAM diagnosis. RESULTS: Seventy-seven out of 131 patients underwent a PET/CT for OC screening. The performance of the PET/CT in patients with myositis at disease onset yielded an area under the curve ROC of 0.87 (0.73-0.97) for CAM diagnosis. Invasive procedures in 7 (9%) patients without a final diagnosis of cancer did not cause derived complications. Patients not evaluated for OC did not develop cancer after a median follow-up of 3.3 years (1.7-6.7). CONCLUSION: Cancer screening strategy should be individualized. PET/CT at myositis onset seems to be an efficient approach to rule out CAM. This practice does not seem to significantly increase harm to patients related to the additional tests needed to clarify inconclusive results.

Management of Cancer-Associated Myositis.

Purpose of the Review: Cancer-associated myositis (CAM) is defined as when cancer appears within 3 years of myositis onset. Dermatomyositis and seronegative immune-mediated necrotizing myopathy are the phenotypes mostly related to cancer. In general, treatment principles in myositis patients with and without CAM are similar. However, some aspects of myositis management are particular to CAM, including (a) the need for a multidisciplinary approach and a close relationship with the oncologist, (b) the presence of immunosuppressive and antineoplastic drug interactions, and (c) the role of the long-term immunosuppressive therapy as a risk factor for cancer relapse or development of a second neoplasm. In this review, we will also discuss immunotherapy in patients treated with checkpoint inhibitors as a treatment for their cancer. Recent Findings: Studies on cancer risk in patients treated with long-term immunosuppressive drugs, in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis, and in solid organ transplant recipients have shed some light on this topic. Immunotherapy, which has been a great advance for the treatment of some types of malignancy, may be also of interest in CAM, given the special relationship between both disorders. Summary: Management of CAM is a challenge. In this complex scenario, therapeutic decisions must consider both diseases simultaneously. Supplementary Information: The online version contains supplementary material available at 10.1007/s40674-022-00197-2.

Radiography-based triage for COVID-19 in the Emergency Department in a Spanish cohort of patients.

Background: Strategies to determine who could be safely discharged home from the Emergency Department (ED) in COVID-19 are needed to decongestion healthcare systems. Objectives: To describe the outcomes of an ED triage system for non-severe patients with suspected COVID-19 and possible pneumonia based on chest X-ray (CXR) upon admission. Material and methods: Retrospective, single-center study performed in Barcelona (Spain) during the COVID-19 peak in March-April 2020. Patients with COVID-19 symptoms and potential pneumonia, without respiratory insufficiency, with priority class IV-V (Andorran triage model) had a CXR upon admission. This approach tried to optimize resource use and to facilitate discharges. The results after adopting this organizational approach are reported. Results: We included 834 patients, 53% were female. Most patients were white (66%) or Hispanic (27%). CXR showed pneumonia in 523 (62.7%). Compared to those without pneumonia, patients with pneumonia were older (55 vs 46.6 years old) and had a higher Charlson comorbidity index (1.9 vs 1.3). Patients with pneumonia were at a higher risk for a combined outcome of admission and/or death (91 vs 12%). Death rates tended to be numerically higher in the pneumonia group (10 vs 1). Among patients without pneumonia in the initial CXR, 10% reconsulted (40% of them with new pneumonia). Conclusion: CXR identified pneumonia in a significant number of patients. Those without pneumonia were mostly discharged. Mortality among patients with an initially negative CXR was low. CXR triage for pneumonia in non-severe COVID-19 patients in the ED can be an effective strategy to optimize resource use.

Introducción: La pandemia de COVID-19 conlleva una alta ocupación de los servicios de urgencias (SU). Se requieren nuevas estrategias para optimizar la gestión de estos recursos. Objetivos: Describir los resultados de un sistema de triaje en urgencias para pacientes no graves con sospecha de COVID-19 y posible neumonía, basado en la radiografía de tórax (RT). Material y métodos: Estudio retrospectivo, unicéntrico realizado en Barcelona (España) entre marzo y abril de 2020. Se realizó una RT al ingreso en SU de pacientes con síntomas de COVID-19 y sospecha de neumonía, sin insuficiencia respiratoria, con una prioridad clase IV-V (sistema andorrano de triaje). Esta medida pretende optimizar los recursos y facilitar las altas. Se reportan los resultados tras adoptar esta estrategia. Resultados: Se incluyeron 834 pacientes (53% mujeres, 66% caucásicos, 27% hispánicos). La RT mostró neumonía en 523 (62,7%). Comparados con los pacientes sin neumonía, los que sí la padecían eran mayores (55 vs. 46,6 años), con un índice de comorbilidad de Charlson más elevado (1,9 vs. 1,3) y con mayor riesgo de ingreso y/o muerte (91 vs. 12%). La mortalidad fue numéricamente mayor en el grupo con neumonía (10 vs. 1). El 10% de los pacientes sin neumonía en RT consultaron de nuevo al SU (40% con neumonía). Conclusión: La RT identificó neumonía en múltiples pacientes. Los que no tenían neumonía fueron mayoritariamente dados de alta. La mortalidad entre pacientes con RT negativa fue baja. La RT como triaje para neumonía en pacientes con COVID-19 no grave puede ahorrar recursos.

Radiography-based triage for COVID-19 in the Emergency Department in a Spanish cohort of patients.

BACKGROUND: Strategies to determine who could be safely discharged home from the Emergency Department (ED) in COVID-19 are needed to decongestion healthcare systems. OBJECTIVES: To describe the outcomes of an ED triage system for non-severe patients with suspected COVID-19 and possible pneumonia based on chest X-ray (CXR) upon admission. MATERIAL AND METHODS: Retrospective, single-center study performed in Barcelona (Spain) during the COVID-19 peak in March-April 2020. Patients with COVID-19 symptoms and potential pneumonia, without respiratory insufficiency, with priority class IV-V (Andorran triage model) had a CXR upon admission. This approach tried to optimize resource use and to facilitate discharges. The results after adopting this organizational approach are reported. RESULTS: We included 834 patients, 53% were female. Most patients were white (66%) or Hispanic (27%). CXR showed pneumonia in 523 (62.7%). Compared to those without pneumonia, patients with pneumonia were older (55 vs 46.6 years old) and had a higher Charlson comorbidity index (1.9 vs 1.3). Patients with pneumonia were at a higher risk for a combined outcome of admission and/or death (91 vs 12%). Death rates tended to be numerically higher in the pneumonia group (10 vs 1). Among patients without pneumonia in the initial CXR, 10% reconsulted (40% of them with new pneumonia). CONCLUSION: CXR identified pneumonia in a significant number of patients. Those without pneumonia were mostly discharged. Mortality among patients with an initially negative CXR was low. CXR triage for pneumonia in non-severe COVID-19 patients in the ED can be an effective strategy to optimize resource use.

Anti-Cortactin Autoantibodies Are Associated With Key Clinical Features in Adult Myositis But Are Rarely Present in Juvenile Myositis.

OBJECTIVE: To define the prevalence and clinical phenotype of anti-cortactin autoantibodies in adult and juvenile myositis. METHODS: In this longitudinal cohort study, anti-cortactin autoantibody titers were assessed by enzyme-linked immunosorbent assay in 670 adult myositis patients and 343 juvenile myositis patients as well as in 202 adult healthy controls and 90 juvenile healthy controls. The prevalence of anti-cortactin autoantibodies was compared among groups. Clinical features of patients with and those without anti-cortactin autoantibodies were also compared. RESULTS: Anti-cortactin autoantibodies were more common in adult dermatomyositis (DM) patients (15%; P = 0.005), particularly those with coexisting anti-Mi-2 autoantibodies (24%; P = 0.03) or anti-NXP-2 autoantibodies (23%; P = 0.04). In adult myositis, anti-cortactin was associated with DM skin involvement (62% of patients with anti-cortactin versus 38% of patients without anti-cortactin; P = 0.03), dysphagia (36% versus 17%; P = 0.02) and coexisting anti-Ro 52 autoantibodies (47% versus 26%; P = 0.001) or anti-NT5c1a autoantibodies (59% versus 33%; P = 0.001). Moreover, the titers of anti-cortactin antibodies were higher in patients with interstitial lung disease (0.15 versus 0.12 arbitrary units; P = 0.03). The prevalence of anti-cortactin autoantibodies was not different in juvenile myositis patients (2%) or in any juvenile myositis subgroup compared to juvenile healthy controls (4%). Nonetheless, juvenile myositis patients with these autoantibodies had a higher prevalence of "mechanic's hands" (25% versus 7%; P = 0.03), a higher number of hospitalizations (2.9 versus 1.3; P = 0.04), and lower peak creatine kinase values (368 versus 818 IU/liter; P = 0.02) than those without anti-cortactin. CONCLUSION: The prevalence of anti-cortactin autoantibodies is increased in adult DM patients with coexisting anti-Mi-2 or anti-NXP-2 autoantibodies. In adults, anti-cortactin autoantibodies are associated with dysphagia and interstitial lung disease.

Role of autoantibodies in the diagnosis and prognosis of interstitial lung disease in autoimmune rheumatic disorders.

Interstitial lung disease (ILD) has been recognized as a frequent manifestation associated with a substantial morbidity and mortality burden in patients with autoimmune rheumatic disorders. Serum autoantibodies are considered good biomarkers for identifying several subsets or specific phenotypes of ILD involvement in these patients. This review features the role of several autoantibodies as a diagnostic and prognostic biomarker linked to the presence ILD and specific ILD phenotypes in autoimmune rheumatic disorders. The case of the diverse antisynthetase antibodies in the antisynthease syndrome or the anti-melanoma differentiation-associated 5 protein (MDA5) antibodies as a marker of a severe condition such as rapidly progressive ILD in patients with clinically amyopathic dermatomyositis are some of the associations herein reported in the group of myositis spectrum disorders. Specific autoantibodies such as the well-known anti-topoisomerase I (anti-Scl70) or the anti-Th/To, anti-U11/U12 ribonucleoprotein, and anti-eukaryotic initiation factor 2B (eIF2B) antibodies seems to be specifically linked to ILD in patients with systemic sclerosis. Overlap syndromes between systemic sclerosis and myositis, also have good ILD biomarkers, which are the anti-PM/Scl and anti-Ku autoantibodies. Lastly, other not so often reported disorders as being associated with ILD but recently most recognized as is the case of rheumatoid arthritis associated ILD or entities herein included in the miscellaneous disorders section, which include anti-neutrophil cytoplasmic antibody-associated interstitial lung disease, Sjögren's syndrome or the mixed connective tissue disease, are also discussed.

Malignancy and myositis, from molecular mimicry to tumor infiltrating lymphocytes.

Cancer-associated dermatomyositis provides a unique opportunity to explore the relationship between autoimmunity and cancer. In this review, we describe the related epidemiological issues, considering the various currently accepted myositis phenotypes, their link with cancer, and the possible mechanisms leading to this relationship. We discuss current evidence regarding the role of molecular mimicry, somatic DNA tumor mutations, and the PD-1/PD-L1 pathway in the association between cancer and myositis. We also review tumor-infiltrating lymphocytes as a relevant factor to be evaluated in cancer-associated myositis, their interaction with tumor neoantigens, and the tumor mutational burden, all of which have implications for the treatment of these patients with immunotherapy. Finally, we discuss clinical scenarios related to the relationship between cancer and myositis, delineating a comprehensive theory linking autoimmunity and cancer.