Myositis-specific Antibodies Research Articles

P047 The triple M threat of check-point inhibitors - an emerging overlap syndrome

Abstract Background/Aims The objective of this abstract is to raise awareness on an emerging overlap syndrome of life-threatening immune-related adverse events, manifesting as a triad of myositis, myocarditis and myasthenia gravis in immune check-point inhibitor (ICI) treated patients. It highlights the success of combination, aggressive and prompt immunosuppression with high dose intravenous steroid, cyclophosphamide, rituximab and intravenous immunoglobulin therapy, in two patients presenting at Guy’s and St Thomas’s Hospital, London with this overlap syndrome following pembrolizumab therapy. Methods Case presentation. Case 1: 75-year-old Caucasian gentleman receives one dose of pembrolizumab for metastatic melanoma. Two weeks later, he presents with myalgia, weakness, elevated CK 10,000. Troponin T is raised 459, ECG shows right bundle branch block (RBBB) and on day 3, he rapidly descends into complete heart block then cardiac arrest. Return of spontaneous circulation is obtained and a permanent pacemaker (PPM) inserted. On day 6, myocardial biopsy confirms acute myocarditis. He develops progressive muscle weakness, dysphagia and Type 2 respiratory failure. He receives 3 doses of IV methylprednisolone, in addition to intravenous immunoglobulins (IVIG) and intravenous cyclophosphamide. EMG shows mild myopathic features, positive AChR antibody, SSA/Ro60 and myositis-specific SRP antibodies and he becomes dependent on non-invasive ventilation. He commences pyridostigmine for myasthenia gravis. On day 19 two doses 1g Rituximab two weeks apart is administered. Monthly IVIG continues for three months and he completes 6 cycles of 500mg cyclophosphamide. A year following discharge, he is maintained on prednisolone 5mg OD with no additional immunosuppression and significantly improved muscle strength. Case 2: 77-year-old Caucasian gentleman receives one dose of pembrolizumab for metastatic melanoma. Four weeks later, he presents with myalgia, bilateral ptosis, muscle weakness and breathlessness. Bloods show CK 6467, troponin T 1058. He promptly receives 3 doses of IV methylprednisolone in addition to IVIG. A PPM is inserted electively as ECGs show RBBB and intermittent bradyarrhythmias. His anti-Ro/SSA-52 antibody is positive and AChR and myositis-specific antibodies are negative. He trials neostigmine due to persistent ptosis. On Day 6, muscle biopsy confirms immune-mediated necrotising myositis and he commences intravenous cyclophosphamide 500mg followed by 5 further cycles. On day 7, 1g intravenous rituximab is administered and repeated two weeks later, additional to monthly IVIG for five months. 6 months later, his CK has normalised and he has no residual muscle weakness. Results n/a Conclusion Although a rare complication of ICIs, this triad of myositis, myocarditis and myasthenia gravis can be potentially severe and fatal. With ICI reshaping the prognosis of several cancers and pembrolizumab gaining recent further approvals, we will increasingly encounter this therapeutic challenge. Therefore, raising awareness of this overlap syndrome amongst rheumatologists is even more critical to allow for prompt recognition and treatment with immunosuppression. Disclosure A. Mootoo: None. A. Masood: None. P. Maghsoudlou: None. D. D'Cruz: None.

P043 Challenges in the diagnosis and management of immune-mediated necrotizing myopathy in a patient on long-term statins

Abstract Background/Aims Statins are very common medications prescribed for cardiovascular disease prevention and with their ever-increasing use; we expect a significant increase in even the rarest side-effects. Immune-mediated necrotising myopathy (IMNM) is a rare type of autoimmune myopathy characterised by relatively severe proximal weakness and is most associated with the development of anti-HMGCoAR (3-hydroxy-3-methylglutaryl CoA Reductase) autoantibodies in statin users. The objective of this clinical case report is to highlight this rare condition to avoid incorrect diagnosis, particularly in primary care, to ensure prompt and specific management. Methods A 51-year-old female presented to her GP with gradual onset muscle weakness particularly around her shoulders and legs. She had a history of hypercholesterolemia, for which she had been on atorvastatin 20mg daily for 4 years. Results Following a blood test by her GP, a raised CK of 16,670 iU/L prompted a hospital admission due to suspected skeletal muscle damage. MRI scan of thighs showed features of myositis and muscle biopsy showed necrotic regenerating muscle fibres with lymphohistiocytic inflammation consistent with necrotizing myopathy. Blood tests revealed positive anti-HMGCoAR antibodies (negative ANA, DNA, ENA & other myositis-specific antibodies) confirming a diagnosis of anti-HMGCoAR IMNM. Atorvastatin was stopped and treatment was initiated with high-dose IV methylprednisolone followed by oral prednisolone tapering course. She showed only minor improvement in symptoms over the initial 6 weeks. Methotrexate was then added, with gradual improvement in her symptoms and normalization of CK over the next 6 months. Conclusion IMNM is unique in that it does not improve with statin discontinuation alone, and usually requires a combination of steroid and steroid-sparing immunosuppressant. Early diagnosis is crucial as commencing treatment early leads to better outcomes in patients. Anti-HMGCoAR antibodies are highly specific for this condition and not associated per se with hyperlipidaemia, self-limiting statin side effects or genetic muscle disease. In patients presenting with muscle weakness who are taking statins, it is beneficial to perform anti-HMGCoAR antibody test (especially if persistent symptoms despite statin cessation) to promptly differentiate this rare condition from more common but less severe statin related myotoxicities. Disclosure F. Khan: None. A. Kuttikat: None.

P067 Covid- 19 infection as a trigger for immune inflammatory myositis

Abstract Background/Aims Increasing experience in managing patients with COVID-19 infection has demonstrated the development of autoimmune phenomena following infection. We describe a patient with preceding COVID-19 infection who presented with inflammatory immune myositis, positive myositis antibodies and a normal creatine kinase. Methods N/A Results A 61-year-old Caucasian female presented feeling generally unwell and with weakness. She had COVID-19 infection 4 months prior, which necessitated admission to the Intensive Care Unit (ITU), treatment with dexamethasone and oxygen and subsequent discharge with home continuous positive airway pressure (CPAP). Other co-morbidities included atrial fibrillation, chronic kidney disease stage three, hypertension, obesity, recent pulmonary embolism, obstructive sleep apnoea, chronic lymphoedema and hypercholesterolaemia on atorvastatin. Her mobility had been gradually reducing over the previous months to now requiring a wheelchair. Neurological examination demonstrated bilateral proximal lower limb weakness, power 3/5 and an unsafe swallow, for which a naso-gastric tube was inserted. A non-specific erythematous pruritic rash was noted on the arms. Full body Computerised tomography (CT) and Magnetic Resonance Imaging (MRI) of the brain and spine were unremarkable. Creatinine kinase (CK) was within normal limits at 81, and C-reactive protein (CRP) was mildly raised at 36. C3 was low at 0.67 and C4 low at 0.03. Cryoglobulins were not detected. She was positive for antinuclear antibody (ANA) (1:320 titre), Ro-52, PM-Scl75, and anti-La. Anti-dsDNA was negative. Electromyography could not be performed due to the presence of chronic lymphoedema. MRI showed symmetrical STIR hyperintense signal changes in the quadriceps muscles bilaterally. A muscle biopsy showed a small focus of mild lymphocyte infiltration in the endomysial connective tissue, mild increase in acid phosphatase expression in many fibres in dotlike pattern, overexpression of HLA-ABC with deposits of complement found in in endomysial capillaries, consistent with a diagnosis of inflammatory myopathy. Following commenced of 60 mg prednisolone daily, there was a marked improvement in swallowing and the NG tube was removed. A positron emission tomography (PET) scan showed non-specific marrow, splenic and adrenal hyperplasia. The patient was then started on mycophenolate mofetil (MMF), but was switched to azathioprine due to side effects. On review following discharge, the patient continues to require a wheelchair to mobilise, but there has been improvement in her swallow and she reports feeling better within herself. Conclusion Inflammatory myositis is a rare sequela of COVID-19 infection. The development of myositis-specific antibodies post infection has previously been described. This case highlights the significant dysphagia and debility despite a normal CK and the need for a high index of suspicion. Possible triggers of an inflammatory response predisposing to autoimmune phenomena include molecular mimicry, bystander activation, exposure of previously hidden epitopes to activated T cells, activation of Toll-like receptors and activation of the complement system. Disclosure G. Bartminski: None. A. Vijayan: None. K. Beharry: None. D. De Lord: None.

The Expression of Cytokine Profiles and Related Receptors in Idiopathic Inflammatory Myopathies.

Background: Cytokines play a vital role in the pathogenesis of idiopathic inflammatory myopathies (IIMs). Here, we investigated the expression of serum cytokine profiles in untreated IIMs and their correlations with clinical indicators, and further studied the expression of related cytokines receptors in IIMs. Methods: The Human 48-Plex Luminex assay for cytokines was performed in the serum of IIMs, including 93 untreated and 18 follow-up (39 samples) patients, and 32 healthy controls (HC). Mann-Whitney U test with bonferroni adjusted was used to identify the differentially expressed cytokines among groups. Celltalker software was used to identify the receptors of differentially expressed cytokines. The expression of receptors was further validated by published GEO datasets (muscle, blood and skin), RT-qPCR, western blot and flow cytometry. Results: The serum levels of Eotaxin, IL7, IL18, IP10, MCP1, MCSF, MIG and SCGFβ were elevated in the 93 untreated patients. Except for IL7, all other cytokines were decreased after treatment and their levels were positively correlated with clinical indices such as LDH, ESR, CRP, ALT, IgA, AST and IgG while negatively correlated with albumin and MMT8. According to the serum myositis-specific antibodies (MSAs), patients were classified into three groups: anti-ARS (Jo-1, OJ, EJ, PL7, PL12), anti-MDA5 positive, and anti-TIF1γ positive. Compared with HC, the levels of IP10 and MIG were increased in three groups. Moreover, IL18 and MSCF were increased in anti-ARS patients, and CTACK, Eotaxin, IL1Rα, IL7, IL18, MCP1, MCP3, MCSF and SCGFβ were elevated in anti-MDA5 patients. Twenty receptors of the 8 differentially expressed cytokines were matched by celltalker software, among them, IL18R1 and CCR1 were up-regulated in blood, muscle and skin of IIMs from the analysis of GEO published datasets. RT-qPCR and western blot further validated IL18R1 was upregulated in the muscle tissues of dermatomyositis. The number of IL18R1+CD4+ cells was increased while IL18R1+CD8+ cells was decreased in peripheral blood of anti-MDA5 patients. Conclusion: This study showed that cytokine profiles were significantly changed in IIMs, and different MSA groups had unique cytokine expression patterns. The levels of some cytokine were correlated with clinical indices. The IL18 receptor IL18R1 might play important roles in IIMs.

Update on Cutaneous Signs to Assist in the Diagnosis of Dermatomyositis.

Dermatomyositis (DM) is a heterogeneous idiopathic inflammatory myopathy that can be challenging to diagnose. Learning about the cutaneous manifestations in DM can assist with prompt diagnosis as well as subgroup classification. This review highlights recent data regarding cutaneous signs in DM and their associations with myositis-specific antibodies (MSAs). Several novel DM skin signs have recently been reported. Novel and confirmatory data have helped to define more clearly the associations between various cutaneous manifestations and MSAs. Awareness of the diverse cutaneous phenotypes can help with the timely diagnosis of DM. As some MSAs are associated with atypical skin features and/or characteristic patterns of clinical findings, knowledge of these associations can help clinicians to recognize DM patients. Understanding how the prevalence and presentation of various cutaneous signs differ among ethnically diverse patients is a high priority for further study.

Clinical value of cancer-associated myositis-specific antibodies, anti-transcriptional intermediary factor 1-γ, and anti-nuclear matrix protein 2 antibodies in a retrospective cohort of dermatomyositis/polymyositis in a Japanese community hospital.

Among the myositis-specific antibodies (MSA), anti-transcriptional intermediary factor 1 (TIF1)-γ and anti-nuclear matrix protein 2 (NXP2) antibodies are reportedly associated with cancer-associated myositis (CAM). We aimed to investigate patient characteristics of CAM and the clinical role of cancer-associated MSA (caMSA) in a retrospective cohort from a city hospital. All patients visiting our department between April 2014 and October 2021 with newly diagnosed dermatomyositis, polymyositis, and clinically amyopathic dermatomyositis were included. Anti-TIF1-γ and anti-NXP2 antibodies were collectively considered as caMSA. First, we compared clinical characteristics in CAM, defined as cases showing onset or recurrence of malignancy within 5years, versus non-CAM. Second, we investigated independent risk factors for CAM. Third, we compared clinical characteristics with and without caMSA within CAM. Finally, we investigated whether caMSA was predictive of poor prognosis. The cohort of 39 patients included 12 (30.7%) CAM cases. Compared with non-CAM, CAM had significantly more dermatomyositis and higher frequencies of dysphagia, anti-TIF1-γ antibody, and caMSA. Using logistic regression analysis, caMSA was an independent risk factor for CAM. In a comparison between caMSA and non-caMSA within CAM, caMSA was associated with higher frequencies of stage ≥ II. However, caMSA did not necessarily indicate a poor prognosis. Only caMSA represented an independent risk factor for CAM and showed a significant association with advanced cancer. Key Points • Cancer-associated MSA was an independent risk factor for cancer-associated myositis. • Cancer-associated MSA was associated with advanced cancer.

Clinical Profile of Anti-Transcription Intermediary Factor-1 Gamma-Positive Adults from a Single Tertiary Care Center

Anti-transcription intermediary factor-1 γ (TIF-1 γ) antibody is a myositis-specific antibody. These cases had specific clinical features in the past studies. There is no published data on such patients from South Asia. We retrospectively looked at data from patients with positive anti-TIF-1 γ antibodies from our hospital database between May 2019 and October 2020. Their clinical presentation, muscle and extra muscular involvement, investigations, presence of malignancy, and treatment with subsequent follow-up were retrieved using the electronic medical records. TIF-1 γ was rare at our center and was 2.46% out of the total positive myositis immunoblot results. Seven adult patients had significant anti-TIF-1 γ positivity. Five out of them had clinical muscle weakness; none had severe or respiratory muscle weakness. No patients had cancer-associated myositis. The skin was the most common extra muscular organ involved. The absence of cancer-associated myositis with anti-TIF-1 γ subjects in our series may represent the difference in phenotype in the South Asian population.

Myositis-specific autoantibodies in clinical practice: Improving the performance of the immunodot

Background/objectivesIdiopathic inflammatory myopathies (IIM) diagnosis and sub-classification can be improved by detection of myositis specific antibodies (MSA) as a first step in diagnosis. However, when using semi-quantitative immunodots for MSA detection, clinical assay performance needs to be improved. MethodsA retrospective study was done for the “myositis” and “synthetase” immunodots (SRP, NXP2, TIF1gamma, SAE1/2, Mi2, MDA5, Jo1, PL7, PL12, EJ, OJ, KS, ZO and HA) from D-Tek used for 270 patients who had tested positive for MSA in a tertiary laboratory hospital. ResultsResults from this analysis revealed: (i) none of the 60 healthy controls presented MSA; (ii) a low assay specificity among patients who tested positive for MSA, 128/270 (47%) were labeled IIM based on the manufacturer's recommended threshold; (iii) in non-IIM patients (53%), the MSA spectrum overlaps predominantly with other autoimmune diseases or idiopathic interstitial lung disease; and (iv) use of a clinical cut-off improves assay specificity for anti-SRP, anti-NXP2, anti-MDA5, anti-Jo1 and anti-PL7 Abs. ConclusionDetermining the clinical threshold of the semi-quantitative immunodot assay for MSA is effective for improving its capacity to discriminate IIM from non-IIM and, when IIM diagnosis is excluded, another autoimmune disease or an idiopathic interstitial lung disease should be considered in front of a positive MSA.

Periorbital rash and scaly plaques in a 13-year–old boy

Periorbital rash and scaly plaques in a 13-year–old boy

The Role of Myositis-Specific Autoantibodies in the Dermatomyositis Spectrum.

Dermatomyositis (DM) is a systemic autoimmune disease that affects skeletal muscles, the skin, and the lungs. It is characterized by autoantibodies, tissue inflammation, parenchymal cell damage, death, and vasculopathy. In terms of epidemiology, DM affects both children and adults. The current pathophysiology of DM is described as an autoimmune attack on the afflicted organs driven by environmental variables such as UV exposure, medications, infections, and lifestyle choices in genetically predisposed people. DM is also a paraneoplastic condition, which means that cancer may arise before, along with, or following the development of the symptoms of DM.Myositis-specific autoantibodies are associated with phenotypical features and are used for sub-classification of dermatomyositis patients. Because the risk of interstitial lung disease (ILD), internal malignancy, destructive disease trajectory, and maybe a response to medication differs by DM myositis-specific antibody (MSA) group, a better knowledge of MSAs and the validation and standardization of tests employed for detection is crucial for improving diagnosis and treatment. The diagnostic sensitivity and specificity of tests for various MSAs are not ideal, just like with any other test. However, more antibody tests are anticipated to make their way into formal schemata for diagnosis and actionable risk assessment in DM due to worldwide standardization and more extensive research. In this review, we outline crucial aspects for interpreting clinical and pathologic relationships with MSA in DM and critical knowledge and practice gaps that will optimize the clinical benefit and utility of MSAs as diagnostic and prognostic markers.

Myositis-specific Antibodies: Overview and Clinical Utilization.

Purpose of review-To review autoantibodies associated with different subtypes of idiopathic inflammatory myopathy (IIM) and their clinical applications. IIM are a heterogenous group of autoimmune disorders characterized by muscle weakness, cutaneous features, and internal organ involvement. The diagnosis and classification, which is often challenging, is made using a combination of clinical features, muscle enzyme levels, imaging, and biopsy. The landmark discoveries of novel autoantibodies specific to IIM subtypes have been one of the greatest advancements in the field of myositis. The specificity of these autoantibodies has simplified the diagnostic algorithm of IIM with their heterogenous presentation and outdated the earlier diagnostic criteria. Myositis-specific antibodies (MSAs) have improved diagnostics, clinical phenotyping, and prognostic stratification of the subtypes of IIMs. Furthermore, the levels of certain MSAs correlate with disease activity and muscle enzyme levels such that titers may be able to be used to predict disease course and treatment response.

Clinical heterogeneities and prognoses of patients with myositis specific antibody negative dermatomyositis: a retrospective study in China.

The clinical features of myositis specific antibody negative dermatomyositis (MSA negative DM) varied greatly, and there were few reports in the literatures. This study aimed to describe and expand the clinical phenotypes and prognoses of MSA negative DM patients. MSA negative DM patients were identified from January 2010 to June 2020. We retrospectively reviewed the clinical features and laboratory data. The survival status was followed up until July 31. 2020 SPSS version 21.0 and R version 3.6.1 software were used for the statistical analyses. A total of 97 MSA negative DM patients were enrolled. The most common type of rashes was heliotrope rash (80.4%). More than half of the patients (55.7%) had interstitial lung disease (ILD), and seven of them developed rapid progressive ILD. There were eleven patients with tumours. During the follow-up, twelve patients died, of whom 5 (41.7%) died due to infection. Two phenotypes of MSA negative DM patients were identified by cluster analysis. Patients in cluster 1 developed muscle weakness, mechanic's hands, arthritis, and ILD more frequently. Patients in cluster 2 had a higher incidence of heliotrope rashes. Patients in cluster 1 tended to have worse prognoses, wherein the 1-year and 5-year survival rates (81.1% and 78.4%, respectively) were lower than those in cluster 2 (97.6% and 95.2%, respectively), with p value 0.04 and 0.056 respectively. Through cluster analysis, different clinical phenotypes of MSA negative DM patients were determined. The prognoses of the two subgroups were different in terms of survival rate and cause of death.

Machine Learning Algorithms Identify Clinical Subtypes and Cancer in Anti-TIF1γ+ Myositis: A Longitudinal Study of 87 Patients.

BackgroundAnti-TIF1γ antibodies are a class of myositis-specific antibodies (MSAs) and are closely associated with adult cancer-associated myositis (CAM). The heterogeneity in anti-TIF1γ+ myositis is poorly explored, and whether anti-TIF1γ+ patients will develop cancer or not is unknown at their first diagnosis. Here, we aimed to explore the subtypes of anti-TIF1γ+ myositis and construct machine learning classifiers to predict cancer in anti-TIF1γ+ patients based on clinical features.MethodsA cohort of 87 anti-TIF1γ+ patients were enrolled and followed up in Xiangya Hospital from June 2017 to June 2021. Sankey diagrams indicating temporal relationships between anti-TIF1γ+ myositis and cancer were plotted. Elastic net and random forest were used to select and rank the most important variables. Multidimensional scaling (MDS) plot and hierarchical cluster analysis were performed to identify subtypes of anti-TIF1γ+ myositis. The clinical characteristics were compared among subtypes of anti-TIF1γ+ patients. Machine learning classifiers were constructed to predict cancer in anti-TIF1γ+ myositis, the accuracy of which was evaluated by receiver operating characteristic (ROC) curves.ResultsForty-seven (54.0%) anti-TIF1γ+ patients had cancer, 78.7% of which were diagnosed within 0.5 years of the myositis diagnosis. Fourteen variables contributing most to distinguishing cancer and non-cancer were selected and used for the calculation of the similarities (proximities) of samples and the construction of machine learning classifiers. The top 10 were disease duration, percentage of lymphocytes (L%), percentage of neutrophils (N%), neutrophil-to-lymphocyte ratio (NLR), sex, C-reactive protein (CRP), shawl sign, arthritis/arthralgia, V-neck sign, and anti-PM-Scl75 antibodies. Anti-TIF1γ+ myositis patients can be clearly separated into three clinical subtypes, which correspond to patients with low, intermediate, and high cancer risk, respectively. Machine learning classifiers [random forest, support vector machines (SVM), extreme gradient boosting (XGBoost), elastic net, and decision tree] had good predictions for cancer in anti-TIF1γ+ myositis patients. In particular, the prediction accuracy of random forest was >90%, and decision tree highlighted disease duration, NLR, and CRP as critical clinical parameters for recognizing cancer patients.ConclusionAnti-TIF1γ+ myositis can be separated into three distinct subtypes with low, intermediate, and high risk of cancer. Machine learning classifiers constructed with clinical characteristics have favorable performance in predicting cancer in anti-TIF1γ+ myositis, which can help physicians in choosing appropriate cancer screening programs.

Therapeutic plasma exchange for the treatment of refractory necrotizing autoimmune myopathy.

IntroductionNecrotizing autoimmune myopathy (NAM) is strongly associated with pathognomonic autoantibodies targeting 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) or signal recognition particle (SRP), whose levels in turn are correlated with serum creatine kinase (CK) and necrosis. Thus, NAM may be amenable to therapeutic plasma exchange (TPE) to remove pathogenic antibodies and improve patient symptoms.MethodsA retrospective case series and literature review of patients presenting with NAM and undergoing treatment with TPE was performed. Clinical data including patient demographics, symptoms, physical exam findings, muscle biopsy, lower extremity imaging, prior therapy, and duration from diagnosis to TPE initiation were collected retrospectively for adult patients with NAM treated with TPE after failing to respond to immunomodulatory therapy. Laboratory data including change in CK levels and myositis‐specific antibody titers from baseline were measured in some patients.ResultsSix patients (median age at diagnosis 52.5 years, interquartile range [IQR] 35.8‐64.5 years, four male/two female) underwent a median of 7.5 (IQR: 5‐10) TPE procedures with 5% albumin as replacement. All patients exhibited a statistically significant reduction in CK level from pre‐TPE baseline (range: 43.0%‐58.7% reduction). Responses in this cohort were best in patients with antibodies targeting HMGCR and SRP, which are most strongly associated with NAM. These results compare favorably to a literature review of NAM patients (n = 19) treated with TPE, who also exhibited positive clinical and laboratory responses across varying treatment lengths.ConclusionTPE can play a role in the management of NAM, particularly in patients with HMGCR or SRP antibodies who are refractory to pharmacologic immunosuppression.

Spontaneous Intramuscular Hemorrhage in Anti-MDA5 Positive Dermatomyositis: A Case Series and Literature Review.

ObjectiveSpontaneous intramuscular hemorrhage (SIH) is a rare but life-threatening complication associated with dermatomyositis (DM). This study reported a case series of SIH associated with DM. In addition, the characteristics and prognostic effects for this complication were analyzed based on literature review.MethodsWe reported seven cases of anti-melanoma differentiation-associated gene five positive dermatomyositis (MDA5+DM) complicated by SIH in our single-center cohort, and a comprehensive literature review was performed. Clinical characteristics, treatment, and outcome data of all eligible reported cases were summarized. Potential prognostic effects were identified by comparisons between the deceased and survivors.ResultsAmong cumulatively reported patients with DM patients and SIH, the overall mortality was 60.9% (14/23) (including our cases). Fourteen out of nineteen (73.7%) hemorrhagic events occurred within 6 months of disease onset. Anti-MDA5 antibody predominated in those myositis-specific antibodies available cases (8/10), although patients with positive anti-NXP2 and anti-Mi2 have also been documented. Iliopsoas (52.2%, 12/23) was the most frequently involved bleeding location. Bleeding in deep muscles was identified to be associated with poorer prognosis. The mortality of patients with DM and deep muscular hematoma (non-palpable) (80%, 12/15) was significantly higher than that of patients with only superficial muscular hematoma (palpable) (25%, 2/8) (p =0.023).ConclusionSpontaneous hematoma in non-palpable deep muscles probably leads to excess mortality in dermatomyositis, particularly for those with anti-MDA5 antibody, which often occurs within 6 months of disease onset. Clinicians should be vigilant to this rare but potentially fatal complication and carefully balance the risks and benefits of prophylactic anti-thrombotic treatment.

Outcome predictors of immune-mediated necrotizing myopathy-a retrospective, multicentre study.

ObjectivesEvidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-term outcomes of patients with IMNM.MethodsMuscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package.ResultsFemale sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate–severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months.ConclusionEarly IVIG was associated with clinical improvement in the short-term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.

Myositis Antibodies and Interstitial Lung Disease.

Interstitial lung disease (ILD) comprises a heterogeneous group of inflammatory and fibrotic conditions, often resulting in progressive lung function decline and increased mortality. Connective tissue disease (CTD) should be considered in all patients with ILD, as distinguishing between CTD-ILD and other forms of fibrotic lung disease has important therapeutic and prognostic implications. The idiopathic inflammatory myopathies (IIM) represent a CTD subtype of growing interest to ILD experts. The expansion and availability of myositis-specific and myositis-associated antibody testing has allowed for improved disease detection and characterization. In this review, we highlight the relationship between myositis antibodies and ILD. Select forms of IIM, such as the antisynthetase syndrome and clinically amyopathic dermatomyositis can present with rapidly progressive ILD, warranting timely disease diagnosis and management. Disease phenotypes, prevalence, laboratory testing, prognosis, and management strategies are described according to select myositis antibodies. Myositis antibodies provide valuable information for clinicians managing patients with ILD. This review aims to increase awareness of their role in disease detection, pathophysiology, and possibly therapeutics.

Positioning of myositis-specific and associated autoantibody (MSA/MAA) testing in disease criteria and routine diagnostic work-up

Nowadays, the importance of detection of myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) in diagnosis and in delineating disease subsets of idiopathic inflammatory myopathy (IIM) is highly acknowledged by IIM experts. Consequently, MSA/MAA are increasingly integrated in expert-based myositis (sub)classification criteria as well as in routine diagnostics. In contrast, MSA/MAA are under-represented in data-based (sub)classification criteria, mostly related to the lack of sufficient data on the wide spectrum of MSA/MAA in large multicenter cohorts. Unfortunately, the current commercially available assays to detect MSA/MAA show variable analytical and clinical performance characteristics. This challenges the design of prospective multicenter studies on MSA/MAA as well as the optimization of their routine clinical use. Additional validation studies and continuous harmonization initiatives on MSA/MAA detection from the pre-analytical to the post-analytical phase (e.g. from defining request criteria to guidelines for reporting), will be needed to overcome these hurdles. To speed up this process, we encourage close collaborations between IIM clinical experts, laboratory professionals and diagnostic companies.

Genetics and Autoimmunity: Two Sides of the Same Coin or an Epiphenomenon?

Distinguishing hereditary forms of myopathy from certain forms of inflammatory myopathy can be challenging. We present 3 cases where a certain degree of overlap was observed between genetics and autoimmunity. A child with juvenile dermatomyositis where heterozygosity for a pathogenic mutation implicated in LGMD1C resulted in a delayed diagnosis. A young lady with anti-SRP positive insidious proximal polymyositis worsening post-partum, diagnosed eventually as LGMD2. An adolescent child referred for proximal myopathy in view of paternal history of LGMD2 but found to have signs of systemic sclerosis with overlap myositis with excellent recovery on therapy. While improvements in whole genome sequencing and detection of myositis specific antibodies have revolutionised the diagnosis and treatment of these diseases, they are still not robust enough and may cloud good clinical judgement in accurate diagnosis and management. Higher sensitivity of these assays is bringing to the fore the possibility that these diagnoses may not be mutually exclusive and might plausibly be concurrent, pending further investigation. These are three interesting cases depicting the difficulties frequently encountered by rheumatologists and neurologists in distinguishing inflammatory from genetic myopathies.

Clues to Disease Activity in Juvenile Dermatomyositis: Neopterin and Other Biomarkers.

Easily accessible biomarkers are urgently needed to evaluate immune activation in Juvenile Dermatomyositis (JDM). The goal of this retrospective study is to define immunological and clinical differences between untreated JDM patients with either normal or elevated (>10 mmol/L) levels of neopterin, a biomarker of macrophage activation. We included all JDM with neopterin data obtained before initiating medical therapy. We assessed T, B, NK cell populations, muscle enzymes, and disease activity scores for skin (sDAS), muscle (mDAS), total (tDAS), the duration of untreated disease, disease course, and myositis-specific antibody (MSA). Seventy-nine percent of 139 untreated JDM patients had elevated serum neopterin. The group with elevated neopterin had significantly more active disease: tDAS 11.9 vs. 8.1 (p < 0.0001), mDAS 5.8 vs. 3.1 (p < 0.0001), sDAS 6.1 vs. 4.9 (p = 0.0002), aldolase 24.0 vs. 7.6 U/L (p < 0.0001), von Willebrand factor antigen (p < 0.0001), and ESR 19.8 vs. 11.5 mm/hr (p = 0.01). The flow cytometry documented both reduced T cells (1494 vs. 2278/mm3, p = 0.008) and NK cells (145 vs. 240/mm3, p = 0.003). TNFα-308AA/AG polymorphism was more common in children with elevated neopterin than TNFα-308GG (p 0.05). We conclude that the availability of neopterin data will contribute to the rapid assessment of untreated JDM disease activity.