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ObjectivesIn 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.MethodsPhage 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.ResultsAnti-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%, pConclusionsAnti-Sp4 autoantibodies appear to identify a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk.

Patients with anti-melanoma-differentiation-associated 5 (anti-MDA5)-positive dermatomyositis (DM) share several striking similarities to patients with SARS-CoV-2. Our objective was to assess the prevalence of anti-angiotensin converting enzyme-2 (ACE2) immunoglobulin M (IgM) antibodies, found in patients with severe SARS-CoV-2, in two independent anti-MDA5-positive DM cohorts.Anti-ACE2 IgM antibodies were assayed by enzyme-linked immunosorbent assay (ELISA) in two anti-MDA5-positive DM cohorts: a predominantly outpatient North American cohort (n = 52) and a Japanese cohort enriched for new-onset disease (n = 32). Additionally, 118 patients with SARS-CoV-2 with a spectrum of clinical severity were tested for anti-MDA5 antibodies by ELISA.Five of fifty-two (9.6%) North American patients and five of thirty-two (15%) Japanese patients were positive for anti-ACE2 IgM. In the North American cohort, all five patients with anti-ACE2 IgM antibodies had proximal muscle weakness, had interstitial lung disease, were significantly more likely to receive pulse dose methylprednisolone (80% vs 30%, P = 0.043), and had worse forced vital capacity (median 59% predicted vs 78%, P = 0.056) compared with the anti-ACE2-IgM-negative group. In the Japanese cohort, all five anti-ACE2-IgM-positive patients also required pulse dose methylprednisolone, and three of five (60%) patients died. Japanese patients with anti-ACE2 IgM had significantly worse oxygenation, as defined by a lower partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (233 vs 390, P = 0.021), and a higher alveolar-arterial oxygenation gradient (91 vs 23 mm Hg, P = 0.024) than the IgM-negative group.We describe anti-ACE2 IgM autoantibodies in two independent cohorts with anti-MDA5-positive DM. These autoantibodies may be biomarkers for severe disease and provide insight into disease pathogenesis.

Justificación: La criobiopsia pulmonar transbronquial (TBLC) se ha propuesto como un método menos invasivo para obtener un diagnóstico tisular en pacientes con enfermedad pulmonar intersticial (EPI). El rendimiento diagnóstico de la TBLC en comparación con la biopsia pulmonar quirúrgica (SLB) sigue siendo incierto. Objetivos: Este estudio tuvo como objetivo determinar la precisión diagnóstica de la biopsia pulmonar transbronquial (TBLB) con fórceps y de la TBLC en comparación con la SLB para realizar el diagnóstico final con base en una discusión multidisciplinaria (MDD). Métodos: Los pacientes incluidos en el estudio se sometieron a TBLB y TBLC secuenciales, seguidas inmediatamente de SLB. Los casos, anonimizados y sin información sobre el método de biopsia, fueron revisados por un patólogo, quien trabajó a ciegas con respecto a dicha información, y luego discutidos en una conferencia multidisciplinaria. Resultados: Principales: Entre agosto de 2013 y octubre de 2017 se reclutaron 16 pacientes. La concordancia primaria entre TBLC y SLB para el diagnóstico final de MDD fue de 68.75%, con una kappa de Cohen de 0.6 (IC 95%: 0.39, 0.81). La concordancia primaria y la kappa de Cohen de la TBLC frente a la SLB para el diagnóstico final de MDD fueron mucho menores (50%, 0.21 [IC 95%: 0, 0.42] y 18.75%, 0.08 [IC 95%: -0.03, 0.19], respectivamente). La TBLC se asoció con hemorragia leve (hemorragia de grado 1, que requirió aspiración) en 56.2% de los pacientes. Conclusiones: En los pacientes con EPI de tipo incierto según con los datos clínicos y radiográficos, quienes requieren la toma de muestra de tejido para obtener un diagnóstico específico, la TBLC mostró una correlación moderada con la SLB al realizar el diagnóstico con la guía de una MDD. La TBLB mostró mala concordancia con los diagnósticos de la MDD, tanto mediante TBLC como por SLB.

This study investigates cancer risk in idiopathic inflammatory myopathy (IIM) subgroups relative to the general population.We conducted a single center, retrospective cohort study of IIM patients and malignancy. Myositis-specific and -associated autoantibodies were determined by Euroimmun line blot, ELISA and immunoprecipitation. The Surveillance, Epidemiology, and End Results registry was used to compare the observed number of cancers to that expected in the general population, defined as a standardized prevalence ratio (SPR), adjusted for calendar year, age, sex, race, and ethnicity.1172 IIM patients, 203 (17%) with a cancer history, were studied. From cohort enrollment over a median follow-up of 5.2 years, the observed number of IIM patients diagnosed with cancer was increased 1.43-fold, SPR 1.43 (95%CI 1.15-1.77), p=0.002. Within 3 years of IIM-symptom onset, an increased SPR was observed for anti-TIF1γ-positive patients for ovarian and breast cancer (ovarian SPR 18.39 (95%CI 5.01-47.08), p0.001; breast SPR 3.84 (95%CI 1.99-6.71), p0.001). While anti-TIF1γ expectedly had a significantly elevated SPR, only 55% (36/66) of all cancers within 3 years of DM-onset were observed in TIF1γ-positive patients. Other MSAs including anti-Mi2, -SAE, and -NXP2 accounted for the majority of the remaining cancer diagnoses, 17/66 (26%), within 3 years of DM-onset. No cancer association, positive or negative, was observed for patients with anti-synthetase, anti-MDA5, or anti-HMGCR antibodies.In a tertiary referral center population, anti-TIF1γ was most strongly associated with breast and ovarian cancer. Patients with anti-synthetase, anti-MDA5, or anti-HMGCR antibodies had the same cancer risk as the general population. This article is protected by copyright. All rights reserved.

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term “progressive pulmonary fibrosis” (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.

Transbronchial lung cryobiopsy (TBLC) has emerged as a less invasive method to obtain a tissue diagnosis in patients with interstitial lung disease (ILD). The diagnostic yield of TBLC compared to surgical lung biopsy (SLB) remains uncertain.The aim of this study was to determine the diagnostic accuracy of forceps transbronchial lung biopsy (TBLB) and TBLC compared to SLB when making the final diagnosis based on multidisciplinary discussion (MDD).Patients enrolled in the study underwent sequential TBLB and TBLC followed immediately by SLB. De-identified cases, with blinding of the biopsy method, were reviewed by a blinded pathologist and then discussed at a multidisciplinary conference.Between August 2013 and October 2017, we enrolled 16 patients. The raw agreement between TBLC and SLB for the MDD final diagnosis was 68.75% with a Cohen's kappa of 0.6 (95% CI 0.39, 0.81). Raw agreement and Cohen's kappa of TBLB versus TBLC and TBLB versus SLB for the MDD final diagnosis were much lower (50%, 0.21 [95% CI 0, 0.42] and 18.75%, 0.08 [95% CI -0.03, 0.19], respectively). TBLC was associated with mild bleeding (grade 1 bleeding requiring suction to clear) in 56.2% of patients.In patients with ILD who have an uncertain type based on clinical and radiographic data and require tissue sampling to obtain a specific diagnosis, TBLC showed moderate correlation with SLB when making the diagnosis with MDD guidance. TBLB showed poor concordance with both TBLC and SLB MDD diagnoses.