Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

High fatigue scores in patients with idiopathic inflammatory myopathies: a multigroup comparative study from the COVAD e-survey.

Idiopathic inflammatory myopathies (IIMs) confer a significant risk of disability and poor quality of life, though fatigue, an important contributing factor, remains under-reported in these individuals. We aimed to compare and analyze differences in visual analog scale (VAS) scores (0-10 cm) for fatigue (VAS-F) in patients with IIMs, non-IIM systemic autoimmune diseases (SAIDs), and healthy controls (HCs). We performed a cross-sectional analysis of the data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) international patient self-reported e-survey. The COVAD survey was circulated from December 2020 to August 2021, and details including demographics, COVID-19 history, vaccination details, SAID details, global health, and functional status were collected from adult patients having received at least one COVID-19 vaccine dose. Fatigue experienced 1 week prior to survey completion was assessed using a single-item 10 cm VAS. Determinants of fatigue were analyzed in regression models. Six thousand nine hundred and eighty-eight respondents (mean age 43.8 years, 72% female; 55% White) were included in the analysis. The overall VAS-F score was 3 (IQR 1-6). Patients with IIMs had similar fatigue scores (5, IQR 3-7) to non-IIM SAIDs [5 (IQR 2-7)], but higher compared to HCs (2, IQR 1-5; P < 0.001), regardless of disease activity. In adjusted analysis, higher VAS-F scores were seen in females (reference female; coefficient -0.17; 95%CI -0.21 to -13; P < 0.001) and Caucasians (reference Caucasians; coefficient -0.22; 95%CI -0.30 to -0.14; P < 0.001 for Asians and coefficient -0.08; 95%CI -0.13 to 0.30; P = 0.003 for Hispanics) in our cohort. Our study found that patients with IIMs exhibit considerable fatigue, similar to other SAIDs and higher than healthy individuals. Women and Caucasians experience greater fatigue scores, allowing identification of stratified groups for optimized multidisciplinary care and improve outcomes such as quality of life.

Capillary leak syndrome in a patient with cancer-associated anti-transcriptional intermediary factor 1γ dermatomyositis treated with rituximab.

Capillary leak syndrome (CLS) is a rare condition characterised by increased capillary permeability, with subsequent hypoalbuminemia and hypotension, leading to an increased risk of shock and death. We present the case of a patient with anti-transcriptional intermediary factor 1γ dermatomyositis that developed CLS one week after starting treatment with rituximab and prophylactic co-trimoxazole. The patient was admitted to the Intensive Care Unit (ICU), recovered after treatment with intravenous immunoglobulin, albumin, and Ringer lactate, but died a month after the discharge due to a poorly differentiated hepatocarcinoma diagnosed in the ICU.

Respiratory failure due to concomitant interstitial lung disease and diaphragmatic involvement in a patient with anti-MDA5 dermatomyositis: a case report.

Diaphragm myositis is a rare manifestation of idiopathic inflammatory myopathies, barely portrayed in literature despite its potential severity. We describe a 57-year-old Caucasian male with anti-MDA5 positive dermatomyositis, that had a 4-month history of progressive dyspnoea requiring oxygen-therapy, scarcely responsive to prednisolone. Chest high resolution computed tomography (HRCT) showed mild interstitial lung disease (ILD), whereas pulmonary function tests evidenced severe restrictive syndrome with high lung ultrasound score. Diaphragm ultrasound revealed a marked diaphragm dysmotility, confirmed by electromyography (EMG). The patient was treated with intravenous immunoglobulins and mofetil mycophenolate with progressive improvement of dyspnoea, lung volumes and ILD at CT scan. Ultrasound examination also revealed marked improvement of the diaphragmatic disfunction and a reduction of lung ultrasound score. The use of ultrasound may provide a valuable tool in the diagnosis of diaphragm myositis, which may play a major role in the respiratory impairment of these patients. A combined lung and diaphragm examination allowed bedside monitoring of the improvements in both lung aeration and diaphragm contractility.

Idiopathic inflammatory myopathies: one year in review 2021

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare and complex connective tissue diseases, mainly characterised by inflammatory involvement of skeletal muscles. Several other organs may be affected, particularly lungs, heart, skin, gastrointestinal tract and joints, often determining the morbidity and mortality associated with these autoimmune disorders. The course is generally chronic and the onset subacute. This latter aspect, together with the rarity of these conditions, can result in a clinical challenge for the physician with a considerable diagnostic delay. The scientific literature makes continuous advances in the understanding of these diseases, in particular with regards to the pathogenesis, serological findings, diagnostic strategies and therapeutic approaches. The aim of this review is to highlight the most relevant literature contributions published on this topic over the last year.

Anti-Ro52 antibodies positivity in antisynthetase syndrome: a single centre cohort study.

OBJECTIVES: Although antisynthetase antibodies (ARS) are the established markers of the so-called antisynthetase syndrome (ASSD), in these patients the concomitant positivity of anti-Ro52 antibodies, reported in up to the 50% of cases, is not rare. Several studies focused on the effect of different ARS specificities on the evolution of ASSD, the most recent showing no effects. On the contrary, the role of co-occurring anti-Ro52 antibodies in ASSD is still debated. We investigated the potential of anti-Ro52 antibodies in identifying a clinical phenotype of ASSD or influencing prognosis, irrespectively to the underlying ARS specificity. METHODS: Retrospective analysis of clinical, imaging and laboratory characteristics, therapeutic approaches and outcome at baseline and at last follow-up, of 60 ASSD patients progressively enrolled at our Hospital. RESULTS: We identified 34 anti-Ro+ and 26 anti-Ro- ASSD patients. Classic triad prevalence at baseline was similar between the two groups, whereas interstitial lung disease (ILD) (p value=0.01) and myositis (p value=0.03) were significantly more prevalent in anti-Ro52+ and in anti-Ro52- patients at last follow up, respectively. No differences in therapeutic approaches, oxygen need and ILD patterns were observed. Overall mortality was 25% (15 subjects). No differences in mortality, overall and disease related, between anti-Ro52+ and anti-Ro52- patients were observed (p value=0.764), despite the more frequent ILD occurrence in anti-Ro52+ patients. Survival curves were not different at any time point (Log-rank test, p value 0.98). CONCLUSIONS: Anti-Ro52 antibodies affect time course and clinical characteristics of ASSD. Although ILD is significantly more associated to anti-Ro52 antibodies, no difference in mortality was observed compared to anti-Ro52 negative patients.

Rare clinical manifestations in systemic lupus erythematosus: a review on frequency and clinical presentation.

OBJECTIVES: The purpose of this study was to review the frequency and clinical presentation of the rarest clinical manifestations of systemic lupus erythematosus (SLE). METHODS: A list of 6 rare SLE manifestations were defined: gastrointestinal, liver, pulmonary, cardiac, ocular and neurological manifestations. Each topic was assigned to a pair of authors to perform a literature search and article review. RESULTS: In total, 149 articles were included in the literature review: 37 for gastrointestinal manifestations, 6 for liver manifestations, 27 for pulmonary manifestations, 50 for cardiac manifestations, 16 for ocular manifestations, 13 for neurological manifestations. Gastrointestinal disorders included several clinical presentations with variable frequency (from 0.5% to 10.7% of the cases); liver involvement included lupus-related hepatitis (9.3%) and autoimmune hepatitis (2.3%). The rarest pulmonary manifestations identified were shrinking lung syndrome, described in 1.5% of patients, while interstitial lung disease and lupus pneumonia were reported in 4% and 3% of patients respectively. Myocarditis and pulmonary hypertension were also rarely described in SLE patients although ranging from 0.4-16% and 1-14% respectively, depending on the methodology used for its identification. Ocular manifestations in SLE included some rare manifestations (reported in less than 5% of patients) and lupus retinopathy that is described in 1.2-28.8% of patients depending on methods of ascertainment. Aseptic meningitis and chorea were also confirmed as very rare manifestations being reported in less than 1% and in 0.3-2.4% of cases respectively. CONCLUSIONS: The results of this literature review provide the basis for a better understanding of some less-known manifestations of SLE and for stressing the need for a higher awareness in diagnostic and therapeutic protocols regarding these rare disease aspects.

Defining anti-synthetase syndrome: a systematic literature review.

OBJECTIVES: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance. METHODS: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate. RESULTS: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly. CONCLUSIONS: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD.

A Proof-of-Concept Analysis of Plasma-Derived Exosomal microRNAs in Interstitial Pulmonary Fibrosis Secondary to Antisynthetase Syndrome.

Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by the positivity of autoantibodies against different aminoacyl transfer RNA (tRNA) synthetases. Morbidity and mortality of this disease are highly affected by interstitial lung disease (ILD) which is present in about 80% of patients. In this study, we investigated possible differences in 84 immune-related circulating miRNAs between ASSD patients with and without ILD; we enrolled 15 ASSD patients, 11 with ILD (ILD+) and 4 without ILD (ILD-), and 5 patients with idiopathic pulmonary fibrosis (IPF) as an additional control group. All patients were at disease onset and not on therapy at the time of inclusion. Differentially expressed miRNAs were identified in plasma-derived exosomes, using an miRNA PCR array (MIHS-111ZG, Qiagen, Hilden, Germany); miR-30a-5p and miR-29c-3p were upregulated in ASSD-ILD patients compared to patients without lung involvement (adjusted p-value < 0.05). IPF patients showed higher miR-29c-3p expression levels with respect to both ASSD and ASSD-ILD (p = 0.0005), whereas levels of miR-30a-5p were not different. miR-29c-3p and miR-30a-5p are overexpressed in ASSD-ILD+ patients compared with ILD−. These miRNAs are involved in the regulation of inflammation and fibrosis through their action on NF-κB and TGF-ß1. Although the mechanistic role of these miRNAs in ASSD-ILD development has to be elucidated, we suggest that their exosome levels could be useful in identifying patients at risk of ILD.

Telemedicine in rheumatology: a reliable approach beyond the pandemic.

OBJECTIVES: The SARS-CoV-2 outbreak has imposed considerable restrictions on people's mobility, which affects the referral of chronically ill patients to health care structures. The emerging need for alternative ways to follow these patients up is leading to a wide adoption of telemedicine. We aimed to evaluate the feasibility of this approach for our cohort of patients with CTDs, investigating their attitude to adopting telemedicine, even after the pandemic. METHODS: We conducted a telephonic survey among consecutive patients referred to our CTD outpatients' clinic, evaluating their capability and propensity for adopting telemedicine and whether they would prefer it over face-to-face evaluation. Demographical and occupational factors were also collected, and their influence on the answers has been evaluated by a multivariate analysis. RESULTS: A total of 175 patients answered our survey (M/F = 28/147), with a median age of 62.5 years [interquartile range (IQR) 53-73]. About 80% of patients owned a device allowing video-calls, and 86% would be able to perform a tele-visit, either alone (50%) or with the help of a relative (36%). Telemedicine was considered acceptable by 78% of patients and 61% would prefer it. Distance from the hospital and patient's educational level were the strongest predictive factors for the acceptance of telemedicine (P < 0.05), whereas age only affected the mastering of required skills (P < 0.001). CONCLUSION: Telemedicine is a viable approach to be considered for routine follow-up of chronic patients, even beyond the pandemic. Our data showed that older patients would be willing to use this approach, although a proper guide for them would be required.

Severe muscle damage with myofiber necrosis and macrophage infiltrates characterize anti-Mi2 positive dermatomyositis.

OBJECTIVE: The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2-). METHODS: Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2- muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. RESULTS: Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2- DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2- patients [median (IQR) creatine-kinase fold increment: 16 (7-37)vs 3.5 (1-9.9), P <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2- patients [mean 5.3% (5) vs 0.8% (1), P <0.01], but similar to IMNM [5.9% (6), P >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P >0.05], whereas lower macrophage infiltration was found in anti-Mi2- DM [mean 0.4 (0.5), <0.01]. CONCLUSIONS: Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy.

One year in review 2020: idiopathic inflammatory myopathies.

The study of idiopathic inflammatory myopathies (IIMs) is acquiring growing importance among systemic autoimmune diseases and every year several articles are published about this group of diseases. Despite this growing interest, the management of IIMs is still critical due to the relative rarity of the condition. The availability of up-to-date knowledge of the evidence on this subject is essential to correctly understand this condition and provide the best care for the patients. The purpose of this review is to provide an overview of the most relevant literature contributions published in the last year.

One year in review 2019: psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory arthritis belonging to spondyloarthritides (SpA), a group of rheumatologic diseases characterised bya wide spectrum of different clinical manifestations that tend to associate with various comorbidities and that may significantly compromise the quality of life of patients. Nowadays, it is well known how PsA may manifest in different clinical domains, in particular peripheral articular and periarticular involvement, axial involvement, skin and nail psoriasis. Moreover, the majority of patients with PsA develop comorbidities such as inflammatory bowel diseases, uveitis, but also cardiovascular diseases, psychiatric or pulmonary pathologies. The therapeutical armamentarium of PsA has been enriched during the last years, in relation to an advance in the knowledge of the immunological mechanisms at the basis of the disease; in particular, the future frontier of "personalised medicine" could lead to a further improvement in the quality of care of this group of patients. In this paper we review the literature on PsA of 2019 (Medline search of articles published from 1st January 2019 to 31st December 2019).

Thrombocytopenia in idiopathic inflammatory myopathies: a case series analysis.

Idiopathic inflammatory myopathies (IIM) are a group of rare connective tissue diseases (CTDs) deeply affecting patients' prognosis. Extra-muscular involvement is not rare and skin, joints and lung are the most common targets. However, also dyserythropoiesis has been described, carrying relevant issues on patients' management and follow-up, as for example, lymphopenia has been associated with an increased risk of rapid progressive interstitial lung disease in anti-MDA5 positive dermatomyositis. Conversely to systemic lupus erythematosus, thrombocytopenia has only been rarely described in IIM and very few authors focused on its potential prognostic implications. We describe five cases of thrombocytopenia in IIM patients positive for myositis specific (MSA) or associated (MAA) autoantibodies. These reports extend the spectrum of haematological features associated to IIM, focusing also on potential risk factors for thrombocytopenia occurrence.

One year in review 2018: idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIMs) are a group of chronic autoimmune systemic diseases affecting the skeletal muscle and other organs. IIMs are also a complex group of diseases, in some cases, difficult to manage. Literature on IIMs has been growing fairly rapidly and keeping up-to-date on such a topic is of utmost importance for any rheumatologist who looks after IIM patients. Thus, the aim of this review is to summarise the most relevant literature contributions published over the last year on the pathogenesis, serology, diagnosis and treatment of IIMs.