RNA Synthetase Antibodies Research Articles

Contrast of muscle magnetic resonance imaging and pathological findings of muscle tissue in patients with anti-aminoacyl transfer RNA synthetase antibodies.

Methods: Patients with idiopathic inflammatory myopathies (IIMs) diagnosed using the 2017 EULAR/ACR classification criteria in our university between 2005 and 2020 were retrospectively reviewed. IIMs were subclassified into the anti-ARS syndrome (ASSD), immune-mediated necrotizing myositis (IMNM), Dermatomyositis DM and others. Fat-suppressed T2-weighted MRI and muscle biopsy specimens were assessed in IIMs followed by the comparison among the four subgroups. MRI findings were available for 62 patients and histopathological findings were available for 27 patients. Perifascicular atrophy or necrosis in the muscle tissues from the patients with IIM was more frequently observed in patients with subcutaneous and fascial high signal intensity (HSI) on MRI than those without. Four-group comparison among ASSD, IMNM, DM and others revealed HSI in fasciae on MRI was more frequently observed in patients with ASSD and DM than others. Perifascicular atrophy or necrosis in muscle tissues was more frequently observed in patients with ASSD than in others. Patients with ASSD had distinct MRI features compared with anti-ARS negative patients. The fascial high signal intensity on MRI may reflect distinctive pathological features of muscles.

Novel endotypes of antisynthetase syndrome identified independent of anti-aminoacyl transfer RNA synthetase antibody specificity that improve prognostic stratification

ObjectivesTo systemically analyse the heterogeneity in the clinical manifestations and prognoses of patients with antisynthetase syndrome (ASS) and evaluate the transcriptional signatures related to different clinical phenotypes.MethodsA total of 701...

Cutaneous manifestations of anti‐synthetase syndrome: Case series and literature review

AbstractBackgroundAnti‐synthetase syndrome (ASyS) is a rare inflammatory myopathy associated with anti‐aminoacyl transfer RNA synthetase antibodies, and is characterized by a triad of interstitial lung disease, arthritis, and myopathy. ASyS has been considered to represent a subtype of dermatomyositis (DM), however it is not clear whether cutaneous findings overlap in both diseases.ObjectivesWe aimed to characterize mucocutaneous features which should raise suspicion of ASyS and prompt early diagnostic testing.MethodsWe reviewed 28 cases of ASyS in our institution, and retrieved data from 43 articles reporting clinical features of ASyS in the literature.ResultsDermatologic manifestations of ASyS can be categorized as: specific cutaneous signs strongly associated with ASyS (‘Mechanic's hands’, ‘Hiker's feet’); mucocutaneous signs overlapping with other collagenoses; nailfold changes (resembling those of DM and systemic sclerosis); and mucocutaneous signs of undetermined significance. Only 20% had pathognomonic DM signs.ConclusionsDermatologic manifestations of ASyS are heterogeneous and do not always reproduce the pattern seen in DM. Presence of palmar hyperkeratosis (‘Mechanic's hands’), cuticular overgrowth, skin ulcerations and nailfold capillary changes should prompt further diagnostic workup of ASyS. Limitations of our study include inconsistent reporting of dermatologic findings within our series between virtual and in‐person visits. Not all patients were seen in dermatology consultation.

Clinical characteristics and prognostic analysis of idiopathic inflammatory myopathy with positive anti-aminoacyl-tRNA synthetase antibodies: A single center experience.

To identify the differences of clinical characteristics, laboratory findings, and the long-term outcomes in patients with anti-synthetase syndrome (ASS) of different anti-aminoacyl-transfer RNA synthetase antibodies. We retrospectively enrolled 119 patients with ASS, and the clinical characteristics and laboratory findings were collected. Additionally, multivariate COX regression analysis was performed to estimate the risk factors of prognosis in patients with ASS. The frequency of interstitial lung disease (ILD) reached 93.3% in our cohort, of 28 (23.5%) was classified as rapidly progressive (RP)-ILD. The highest incidence of RP-ILD was 36.4% in the PL12 group of ASS patients. The ILD group was characterized by an older age, a lower prevalence of V sign, and a higher prevalence of pulmonary symptoms when contrasted with the non-ILD group. There were statistical differences of clinical significance in arthritis, myositis, mechanic's hands, triad, shawl sign, V sign, and Raynaud's phenomenon among the four subgroups (all p < .05). Additionally, the prevalence rates of arthritis, myositis, mechanic's hands, triad, and V sign in the anti-Jo1 antibody-positive group were significantly higher than anti-Jo1 antibody-negative patients with ASS (all p < .05). Multivariate Cox regression analysis showed mechanic's hands (odds ratio [OR] = 6.47, p < .001), anti-nuclear antibodies (ANA) (OR = 2.13, p = .026), ILD (OR = 10.50, p < .001), and V sign (OR = 0.30, p = .007) were independent factors affecting the prognosis of patients with ASS. The incidences of RP-ILD, arthritis, myositis, triad, mechanic's hands, and shawl sign were more frequent in the anti-Ro52 antibody-positive group than the anti-Ro52 antibody-negative patients with ASS (all p < .05). Patients with ASS accompanied with ILD are highly prevalent. Mechanic's hands, ANA, and ILD may be a potential biomarker for predicting a poor prognosis in patients with ASS. Additionally, the detection of the anti-Ro52 antibody provides valuable insights for managing and predicting disease progression and long-term outcomes.

Antisynthetase syndrome with anti-oj antibody: A Case report and review of literature

Antisynthetase syndrome (ASS) is a rare autoimmune disease characterized by the presence of an anti-aminoacyl transfer RNA synthetase antibody with one or more clinical features. The prevalence of anti-OJ antibodies in ASS is 2%–5%. Information regarding the clinical presentation and evolution of these patients is limited. We report a case of ASS with anti-OJ antibody in a 45-year-old female from India, who presented with arthritis and interstitial lung disease (ILD). She was managed with corticosteroids and intravenous cyclophosphamide. We also described the clinical details of 69 previously reported ASS patients with anti-OJ antibody. Data from these patients including our patient showed that isolated ILD was the most common form of presentation (24%) followed by myositis with ILD (16%), isolated arthritis (15%), and isolated myositis (13%). The prevalence of arthritis, myositis, and ILD, at the disease onset, was 33%, 42%, and 70%, respectively, whereas the overall prevalence was 44%, 77%, and 83%, respectively.

PNEUMONIA MASQUERADING AS ANTI-SYNTHETASE SYNDROME

TOPIC: Lung Pathology TYPE: Fellow Case Reports INTRODUCTION: Anti-synthetase syndrome (ASS) is a rare autoimmune disorder, characterized by anti-aminoacyl transfer RNA synthetase antibodies along with clinical features that can include interstitial lung disease, myositis, Raynaud's phenomenon, non-erosive arthritis, unexplained fever, and/or mechanic's hands. [1] Most patients with ASS with lung involvement present with chronic lung changes, we are describing a case of atypical presentation of ASS lung disease with organizing pneumonia. CASE PRESENTATION: A 60-year-old woman with a history of obstructive sleep apnea, asthma/COPD, and hypothyroidism presented with progressive shortness of breath. The patient had two recent hospitalizations for asthma exacerbation and pneumonia. Chest CT showed patchy scattered ground-glass opacities and consolidative changes with mild traction bronchiectasis changes. Autoimmune workup was positive for anti-SSA (mildly) and ANA but negative for RF, anti-smith, RNP, SSB, SCL70, centromere, PR3, MPO, RNA-Pol 3, and CCP antibodies. Myositis panel was positive for PL-12 Ab. Lung biopsy was consistent with a predominant pattern of organizing pneumonia. In the absence of myositis, the patient was diagnosed with ASS. The patient was initiated on mycophenolic acid and prednisone therapy. Initial pulmonary function tests showed FEV1/FVC is 74, FEV1 is 1.33L (61% of predicted) and FVC is 1.79L (66% of predicted), following treatment repeat PFTs in 3 months showed FEV1/FVC is 68, FEV1 is 1.45L (65% of predicted) and FVC is 2.13L (76% of predicted). Her exercise capacity improved with a six-minute walk test showing a walk distance of 177m with 3 L oxygen before treatment which improved to 435 m with 1 L oxygen post-treatment after 3 months. DISCUSSION: ASS is a group of inflammatory myopathies that requires evidence of anti-aminoacyl transfer RNA synthetase autoantibody and one or more of the following: mechanic's hands, Raynaud's phenomenon, myositis, ILD, arthritis, and/or unexplained fever. [2] Most cases are either misdiagnosed as idiopathic ILD or inflammatory myopathy. CONCLUSIONS: We presented a case of ASS with biopsy-proven organizing pneumonia. Organizing pneumonia is a very rare presentation of ASS and should be kept in mind while evaluating patients with ASS. REFERENCE #1: 1. Stone KB, Oddis CV, Fertig N, Katsumata Y, Lucas M, Vogt M, Domsic R, Ascherman DP. Anti–Jo-1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy. Arthritis & Rheumatism. 2007; 56:3125–3131. [PubMed: 17763431] REFERENCE #2: 2. References Connors GR, Christopher-Stine L, Oddis CV, Danoff SK. Interstitial lung disease associated with the idiopathic inflammatory myopathies: What progress has been made in the past 35 years? Chest. 2010; 138:1464–1474. [PubMed: 21138882] DISCLOSURES: No relevant relationships by Bharat Bhandari, source=Web Response No relevant relationships by Rahat Hussain, source=Web Response No relevant relationships by Soma Sundara Shravan Jyothula, source=Web Response

A narrative review of interstitial lung disease in anti-synthetase syndrome: a clinical approach.

Anti-synthetase syndrome (AS) is a rare autoimmune disorder characterized by the presence of aminoacyl-transfer RNA synthetase antibodies in conjunction with clinical features such as interstitial lung disease (ILD), Raynaud’s phenomenon, nonerosive arthritis, and myopathy. AS distinguishes itself from other inflammatory myopathies by its significant lung involvement and rapidly progressive interstitial lung disease (AS-ILD), therefore the management of AS-ILD requires careful clinical, serologic and radiologic assessment. Glucocorticoids are considered the mainstay of therapy; however, additional immunosuppressive agents are often required to achieve disease control. Patient prognosis is highly dependent on early diagnosis and symptom recognition as the antibody profile is thought to influence therapy response. Since progressive ILD is the leading cause of morbidity and mortality, this review will discuss the clinical approach to patient with suspected AS, with particular emphasis on diagnosis and management of AS-ILD.

The clinical characteristics and predictors of severe digital ischemia in patients with anti-aminoacyl transfer RNA synthetase antibodies.

Severe digital ischemia (SDI), which presents with digital ulcers, necrosis, or gangrene, has been reported to be a rare manifestation of anti-aminoacyl transfer RNA synthetase (ARS) antibody-positive polymyositis/dermatomyositis or anti-synthetase syndrome. A retrospective study was conducted between 2009 and 2020 at our department to investigate the clinical features of anti-ARS antibody-positive patients with SDI and identify their predictors. A total of 46 patients who were positive for anti-ARS antibody were included, four of whom (8.7%) presented with SDI. The characteristics of the patients with SDI were as follows: the median age was 74years, with 75% being female; anti-Jo-1 antibody, Raynaud's phenomenon, interstitial lung disease, and myositis were observed in two (50%), four (100%), four (100%), and three patients (75%), respectively. Next, we reviewed the literature of anti-ARS antibody-positive patients with SDI and investigated the predictors of SDI by analyzing a total of 51 patients, including the previously reported five patients with SDI. Multivariable analyses revealed that Raynaud's phenomenon and myositis independently predicted the development of SDI in patients with anti-ARS antibody. In conclusion, digital ulcers, necrosis, or gangrene seem to be more common presentations in our study, and Raynaud's phenomenon and myositis can predict the complications of SDI in anti-ARS antibody-positive patients.

Clinical manifestations and outcome of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody positive patients with interstitial lung disease.

To analyse the clinical features and risk factors of acute/subacute interstitial pneumonia (A/SIP) and death in patients with positive anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) and positive anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab). Interstitial lung disease (ILD) patients with anti-ARS+ or anti-MDA5+ were recruited. Their demographics, clinical manifestations, laboratory data were collected and they were followed up for 1 year. Risk factors of A/SIP and mortality were analysed. 71 patients with anti-ARS+ ILD and 31 patients with anti-MDA5+ ILD were included. Incidence of ulcerative rash, Gottron's sign, pulmonary infection and A/SIP in the anti-MDA5+ group were significantly higher than those in the anti-ARS+ group, Creatine kinase (CK), leukocyte count, and lymphocyte count were lower, the value of serum ferritin (SF) was higher, and 12-month cumulative survival rate was lower. Advanced age, anti-MDA5+ and low immunoglobulin G (IgG) level were independent predictors of A/SIP. The decreased PaO2 and elevated SF were independent predictors for poor prognosis in A/SIP patients. Compared to anti-ARS+ group, the anti-MDA5+ group was more prone to ulcerative rash, Gottron's sign and pulmonary infection. Patients with anti-MDA5+, advanced age and decreased values of IgG were more likely to have A/SIP, while patients with A/SIP had lower incidence of myositis and arthritis. Mortality of A/SIP patients increased with higher serum ferritin level.

Antisynthetase syndrome-An underdiagnosed entity

Anti-synthetase syndrome is an autoimmune disease, characterized by aminoacyl transfer RNA synthetase antibodies with clinical features that can include interstitial lung disease, myositis, Raynaud’s phenomenon, and arthritis. There is a higher prevalence and increased severity of interstitial lung disease in patients with the anti-synthetase syndrome as compared to other inflammatory myopathies. Diagnosis is made by serological, radiographic, and muscle and/or lung biopsy results. Patients frequently require multi-modality immunosuppressive therapy to manage muscular and pulmonary manifestations of the disease. Careful attention is required to the adverse effects and complications of chronic immunosuppressive therapy, as well as to the disease complications which include progressive interstitial lung disease, pulmonary hypertension, and malignancy. Increased awareness of this syndrome will allow for early diagnosis and treatment improving outcomes in patients.

Cutaneous manifestations of dermatomyositis characterized by myositis-specific autoantibodies.

Dermatomyositis (DM) is an inflammatory myopathy with characteristic skin manifestations, the pathologies of which are considered autoimmune diseases. DM is a heterogeneous disorder with various phenotypes, including myositis, dermatitis, and interstitial lung disease (ILD). Recently identified myositis-specific autoantibodies have been associated with distinct clinical features. For example, anti-melanoma differentiation-associated protein 5 antibodies have a high specificity for clinically amyopathic DM presenting rapidly progressive ILD. Furthermore, anti-transcriptional intermediary factor 1γ antibodies found in patients with juvenile and adult DM are closely correlated with malignancies, especially in elderly patients. Finally, patients with anti-aminoacyl-transfer RNA synthetase antibodies share characteristic clinical symptoms, including myositis, ILD, arthritis/arthralgia, Raynaud’s phenomenon, and fever; thus, the term “anti-synthetase syndrome” is also used. With a focus on the characteristic cutaneous manifestations in each subgroup classified according to myositis-specific autoantibodies, we introduce the findings of previous reports, including our recent analysis indicating that skin eruptions can be histopathologically classified into myositis-specific autoantibody-associated subgroups and used to determine the systemic pathologies of the different types of antibody-associated DM.

Inflammatory myopathy associated with PD-1 inhibitors

ObjectiveTo characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). MethodsWe studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. ResultsIn regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. ConclusionsBased on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

Integrated Diagnosis Project for Inflammatory Myopathies: An association between autoantibodies and muscle pathology.

Inflammatory myopathies are a heterogeneous group of immune-mediated diseases that involve skeletal muscle as well as many other organs. The classification of inflammatory myopathies has been based on clinical diagnoses, pathological diagnoses, and autoantibodies, independently. The clinical phenotypes of inflammatory myopathies are characterized by various autoantibodies that are originally detected by RNA or protein immunoprecipitation. However, since the correlation between histological features and autoantibodies had not been fully elucidated, we created the "Integrated Diagnosis Project for Inflammatory Myopathies" in October 2010. Based on our work and previous studies, the three major subsets of inflammatory myopathies defined by autoantibodies are immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome, and dermatomyositis. IMNM is the pathological entity, characterized by significant necrotic and regeneration muscle fibers with minimal or no inflammatory cell infiltration. The detection of autoantibodies against signal recognition particles or 3-hydroxy-3-methylglutaryl-coenzyme A reductase is important for the diagnosis of IMNM. Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is the clinical entity based on the presence of aminoacyl transfer RNA synthetase antibodies. Perifascicular necrosis is a distinctive hallmark of antisynthetase syndrome in muscle pathology. The diagnosis of dermatomyositis is usually based on clinical features of typical skin rash. Several autoantibodies are associated with specific subsets of dermatomyositis. Myxovirus resistance A expression in the myofiber cytoplasm has a better sensitivity for the diagnosis of dermatomyositis compared to perifascicular atrophy. The screening of autoantibodies has clinical relevance for managing patients with inflammatory myopathies.

The long-term outcome of interstitial lung disease with anti-aminoacyl-tRNA synthetase antibodies

RationaleAnti-aminoacyl transfer RNA synthetase antibodies (anti-ARS) are a group of myositis-specific autoantibodies that are detected in the sera of patients with polymyositis and dermatomyositis (PM/DM) and also in those of patients with idiopathic interstitial pneumonias without any connective tissue disease (CTD), including PM/DM. Although we reported the clinical characteristics of interstitial lung disease with anti-ARS antibodies (ARS-ILD) with and without PM/DM, the long-term prognosis of ARS-ILD remains undetermined. As our previous studies revealed that ARS-ILD without PM/DM was similar to CTD-associated ILD, and that ARS-ILD with PM/DM was radiologically suggestive of a nonspecific interstitial pneumonia (NSIP) pathological pattern, we hypothesized that the prognosis of ARS-ILD might be distinct from that of idiopathic pulmonary fibrosis (IPF) without anti-ARS. ObjectivesTo elucidate the long-term outcome of ARS-ILD with and without PM/DM and compare it to that of IPF. MethodsA two-center retrospective study was conducted. The study population comprised 36 patients with ARS-ILD (8 with PM, 12 with DM, and 16 without myositis throughout the course), 100 patients with IPF without anti-ARS, and 7 patients with NSIP without anti-ARS. The presence of anti-ARS was determined by RNA immunoprecipitation using the sera obtained at the time of diagnosis before specific treatment. Measurements and main resultsDuring the observational period (median 49 months; range, 1–114 months), 7 patients with ARS-ILD (19%; 3 with PM, 1 with DM, and 3 without PM/DM) and 51 patients with IPF (51%) died. Patients with ARS-ILD had better overall survival than those with IPF (log-rank test, P < 0.001) and similar survival compared to those with NSIP (log-rank test, P = 0.59). The prognosis for patients with ARS-ILD was similar between those with and without myositis (log-rank test, P = 0.91). At the median follow-up time of 76.5 months, 14 of the 36 patients with ARS-ILD had deteriorated. Both a decline in forced vital capacity or an initiation of long-term oxygen therapy during the course (odds ratio [OR], 5.34) and acute exacerbation (OR, 28.4) significantly increased the mortality risk. ConclusionsThe long-term outcome of ARS-ILD was significantly better than that of IPF regardless of the presence or absence of myositis.

Association of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease.

We attempted to clarify whether the presence of anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) or anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is associated with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). We retrospectively investigated 22 patients with PM/DM-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab) for whom antibody analysis of conserved serum was possible. We assessed mortality in the first three months as the therapeutic response in the acute phase and compared changes in clinical data for up to one year considered as the chronic phase. We classified the clinical changes over the year into three groups: Improvement (increased % vital capacity [%VC] or diffusing capacity of the lung for carbon monoxide [%DLCO]≥10 or 15%), deterioration (decreased %VC or %DLCO≥10 or 15%), and no change (remainder of the changes). The extent of abnormality demonstrated by high-resolution computed tomography (HRCT) was scored. Positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %DLCO and a decline in the serum KL-6 levels. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by HRCT. Anti-ARS and anti-MDA5 Abs are associated with the therapeutic response of PM/DM-ILD.

Clinical subsets associated with different anti-aminoacyl transfer RNA synthetase antibodies and their association with coexisting anti-Ro52

Objective: To characterize clinical features of polymyositis/dermatomyositis (PM/DM) patients with different anti-aminoacyl transfer RNA synthetase (ARS) antibodies and their association with anti-Ro52.Methods: Autoantibodies in sera from 97 Japanese patients (36 PM, 56 DM, and 5 clinically amyopathic DM), who satisfied Bohan and Peter or modified Sontheimer's criteria, were characterized by immunoprecipitation and enzyme-linked immunosorbent assay. Clinical information was from medical records. Features associated with different anti-ARS and anti-Ro52 antibodies were analyzed.Results: The prevalence of anti-ARS was similar to other studies (Jo-1, 22%; EJ, 4%; OJ, 1%; PL-12, 1%), except for a high prevalence of anti-PL-7 (12%), which allowed us to characterize patients carrying this specificity. Serum creatine kinase >3000 IU/l was less common in anti-PL-7-positive patients (57%) than anti-Jo-1-positive patients (18%) (p = 0.0328) and was not found in anti-EJ-positive individuals. Interstitial lung disease was common in anti-ARS-positive patients (97%) (p < 0.0001 vs. 48% in anti-ARS-negative). Anti-Ro52 antibodies were frequently detected with anti-ARS (59%) (57% in anti-Jo-1, 67% in anti-PL-7) (vs. 21% in anti-ARS-negative, p < 0.0002). Anti-Ro52 was associated with overlap syndrome (26%) (vs. 7% in anti-Ro52-negative, p = 0.0119).Conclusions: Patients with different anti-ARS in combination with anti-Ro52 appear to be associated with distinctive clinical subsets.

Statins and Myotoxic Effects Associated With Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies

Statins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG.We enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies.We established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients’ serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of muscle MRI. Of the 251 patients with MG, 23 were administered statins at the onset of MG. One late-onset MG patient experienced MG worsening after 4-wk treatment with atorvastatin. However, anti-HMGCR antibodies were not detected in the 251 MG patients except for one early-onset MG patient with no history of statin therapy.Anti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin exposure, but they are not associated with the onset or deterioration of MG.

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.