Anti-SAE autoantibody in dermatomyositis: original comparative study and review of the literature.

OBJECTIVE: Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM. METHODS: Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature. RESULTS: Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003). CONCLUSION: Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672.

Comparison of MR T1 and T2 mapping parameters to characterize myocardial and skeletal muscle involvement in systemic idiopathic inflammatory myopathy (IIM).

OBJECTIVES: To compare the performance of magnetic resonance (MR) relaxometry parameters to discriminate myocardial and skeletal muscle inflammation in idiopathic inflammatory myopathy (IIM) patients from healthy controls. MATERIALS AND METHODS: For this retrospective case-control study, 20 consecutive IIM patients (54 ± 18 years, 11 females) with cardiac involvement (troponin level > 50 ng/l) and 20 healthy controls (47 ± 12 years, 9 females) were included. All patients without cardiac MR imaging < 2 weeks prior to the laboratory testings were excluded. T1/T2 relaxation times, as well as T1-derived extracellular volume (ECV), relative tissue T1 shortening ΔT1 = (native T1tissue-post contrast T1tissue)/native T1tissue), and enhancement fraction EHF = (native T1tissue-post contrast T1tissue)/(native T1blood-post contrast T1blood), were compared using Mann-Whitney U test and ROC analysis. RESULTS: All measured MR relaxometry parameters significantly discriminated IIM patients and healthy controls, except T2 in skeletal muscles and ECV in the myocardium. In skeletal muscles, post contrast T1 and T1-derived parameters showed the best performance to discriminate IIM patients from healthy controls (AUC = 0.98 for post contrast T1 and AUC 0.94-0.97 for T1-derived parameters). Inversely, in the myocardium, native T1 and T2 showed better diagnostic performance (AUC = 0.89) than post contrast T1 (AUC = 0.76), ECV (AUC = 0.58), ΔT1 (AUC = 0.80) and EHF (0.82). CONCLUSIONS: MR relaxometry parameters applied to the myocardium and skeletal muscles might be useful to separate IIM patients from healthy controls. However, different tissue composition and vascularization should be taken into account for their interpretation. ΔT1 and EHF may be simple alternatives to ECV in highly vascularized tissues such as the myocardium. KEY POINTS: • MR relaxometry parameters applied to the myocardium and skeletal muscles are highly useful to separate IIM patients from healthy controls. • Different tissue composition and vascularization should be taken into account for T1 and T2 mapping parameter interpretation. • ΔT1 and EHF may be simple alternatives to ECV in highly vascularized tissues such as the myocardium.

Non-invasive differentiation of idiopathic inflammatory myopathy with cardiac involvement from acute viral myocarditis using cardiovascular magnetic resonance imaging T1 and T2 mapping.

BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases with systemic myositis which may involve the myocardium. Cardiac involvement in IIM, although often subclinical, may mimic clinical manifestations of acute viral myocarditis (AVM). Our aim was to investigate the usefulness of the combined analysis of cardiovascular magnetic resonance (CMR) T1 and T2 mapping parameters measured both in the myocardium and in the thoracic skeletal muscles to differentiate AVM from IIM cardiac involvement. METHODS: Sixty subjects were included in this retrospective study (36 male, age 45 ± 16 years): twenty patients with AVM, twenty patients with IIM and cardiac involvement and twenty healthy controls. Study participants underwent CMR imaging with modified Look-Locker inversion-recovery (MOLLI) T1 mapping and 3-point balanced steady-state-free precession T2 mapping. Relaxation times were quantified after endocardial and epicardial delineation on basal and medial short-axis slices, as well as in different thoracic skeletal muscle groups present in the CMR field-of-view. ROC-Analysis was performed to assess the ability of mapping indices to discriminate the study groups. RESULTS: Mapping parameters in the thoracic skeletal muscles were able to discriminate between AVM and IIM patients. Best skeletal muscle parameters to identify IIM from AVM patients were reduced post-contrast T1 and increased extracellular volume (ECV), resulting in an area under the ROC curve (AUC) of 0.95 for post-contrast T1 and 0.96 for ECV. Conversely, myocardial mapping parameters did not discriminate IIM from AVM patients but increased native T1 (AUC 0.89 for AVM; 0.84 for IIM) and increased T2 (AUC 0.82 for AVM; 0.88 for IIM) could differentiate both patient groups from healthy controls. CONCLUSION: CMR myocardial mapping detects cardiac inflammation in AVM and IIM compared to normal myocardium in healthy controls but does not differentiate IIM from AVM. However, thoracic skeletal muscle mapping was able to accurately discern IIM from AVM.

Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: Common Interferon Signature but Distinct NOS2 Expression.

The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti-MDA5(+)-patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti-MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed in anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2-positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti-MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.

High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody.

Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.

Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation.

Histiocytoses are a group of heterogeneous diseases that mostly comprise Langerhans cell histiocytosis (LCH) and non-LCH. The association of LCH with non-LCH is exceptional. We report 23 patients with biopsy-proven LCH associated with Erdheim-Chester disease (ECD) (mixed histiocytosis) and discuss the significance of this association. We compare the clinical phenotypes of these patients with those of 56 patients with isolated LCH and 53 patients with isolated ECD. The average age at diagnosis was 43 years. ECD followed (n = 12) or was diagnosed simultaneously with (n = 11) but never preceded LCH. Although heterogeneous, the phenotype of patients with mixed histiocytosis was closer to that of isolated ECD than to that of isolated LCH (principal component analysis). LCH and ECD improved in response to interferon alpha-2a treatment in only 50% of patients (8 of 16). We found the BRAF(V600E) mutation in 11 (69%) of 16 LCH lesions and in 9 (82%) of 11 ECD lesions. Eight patients had mutations in both ECD and LCH biopsies. Our findings indicate that the association of LCH and ECD is not fortuitous and suggest a link between these diseases involving the BRAF(V600E) mutation.

A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C.

γ-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the γ-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27 years; range 16-38 years) with del525T homozygous mutation of the γ-sarcoglycan gene and no γ-sarcoglycan immunostaining on muscle biopsy were divided into three equal groups to receive three escalating doses of an adeno-associated virus serotype 1 vector expressing the human γ-sarcoglycan gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3 × 10(9) viral genomes in 100 µl, the second group received a single injection of 1.5 × 10(10) viral genomes in 100 µl, and the third group received three simultaneous 100-µl injections at the same site, delivering a total dose of 4.5 × 10(10) viral genomes. No serious adverse effects occurred during 6 months of follow-up. All nine patients became adeno-associated virus serotype 1 seropositive and one developed a cytotoxic response to the adeno-associated virus serotype 1 capsid. Thirty days later, immunohistochemical analysis of injected-muscle biopsy specimens showed γ-sarcoglycan expression in all three patients who received the highest dose (4.7-10.5% positively stained fibres), while real-time polymerase chain reaction detected γ-sarcoglycan messenger RNA. In one patient, γ-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of γ-sarcoglycan expression (<1% positively stained fibres) were also detectable. Expression of γ-sarcoglycan protein can be induced in patients with limb girdle muscular dystrophy type 2C by adeno-associated virus serotype 1 gene transfer, with no serious adverse effects.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature.

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis that may present with pulmonary involvement. We undertook the current study to evaluate the characteristic features of pulmonary involvement in ECD, in the largest single-center series of patients reported to date. METHODS: We performed a retrospective study of the characteristics of 34 consecutive patients with biopsy-proven ECD who were referred to the internal medicine department of Pitié-Salpêtrière Hospital between 1981 and November 2008. RESULTS: Data were obtained from 23 men and 11 women. The median age at the time of diagnosis was 53.7 years (range 16-73 years), and the median followup was 3.5 years (1.4-5.3 years). Eight patients (24%) had pulmonary symptoms. High-resolution computed tomography (HRCT) scans of the chest revealed involvement of lung parenchyma in 18 patients (53%) and of the pleura in 14 patients (41%). Bronchoalveolar lavage fluid analysis revealed the presence of an opalescent aspirate in all the patients studied. Treatment with corticosteroids and/or interferon-α (IFNα) resulted in a marked improvement of the pulmonary lesions in only a single patient. Comparison of the survival between patients with and those without pulmonary involvement yielded no significant difference between the groups (P = 0.82). CONCLUSION: Pulmonary involvement in ECD has been overlooked in previous studies. HRCT reveals typical lesions in most patients. There is no clear response of these lesions to corticosteroids and IFNα. The overall prognosis of the disease is poor, but pulmonary involvement does not appear to be a major prognostic factor in ECD.

Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial.

BACKGROUND: Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis. METHODS: This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45-80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days -15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT02481453. FINDINGS: Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI -10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients. INTERPRETATION: We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus. FUNDING: Institut national de la santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies.

Relationship between change in physical activity and in clinical status in patients with idiopathic inflammatory myopathy: A prospective cohort study.

OBJECTIVE: This study aimed to investigate the relationship between changes in clinical status on daily life physical activity (PA) in patients with idiopathic inflammatory myopathy (IIM). METHODS: Patients with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) or overlap myositis (OM) who presented either a new-onset or relapsing IIM, stable disease on maintenance therapy or were undergoing immunosuppressant tapering were included. Patients were evaluated at inclusion (V0), and at two follow-up visits (V1, 94±12 days from V0; V2, 96±17 days from V1). The American College of Rheumatology/European League against Rheumatism (ACR/EULAR) response criteria was recorded. PA assessed using 14-days raw accelerometry data gathered using a wrist-worn accelerometer after each visit (mean daily Euclidean norm minus 1 g (ENMO) was computed). RESULTS: Fifty-five patients (16 OM, 27 IMNM and 12 DM) were included. At baseline, 67% of patients had an ENMO Z-score less than 1. At inclusion, ENMO mainly correlated with health assessment questionnaire score (HAQ, ρ=-0.51, p<0.01), manual muscle testing 8 (MMT8, ρ=0.42, p<0.01), creatinine level (ρ=0.41, p<0.01), and SF-36 physical functioning score (ρ=0.38, p<0.002). At follow-up, ENMO changes mainly correlated with changes in MMT8, HAQ, SF-36 fatigue, and depression score (all ρ>0.43, all p<0.001). Level of agreement between ACR/EULAR response criteria and changes in PA was 15, 45, and 90% for minimal (n = 13), moderate (n = 20), and major (n = 10) improvements, respectively. CONCLUSION: Baseline PA levels and change in PA correlated with muscle strength and function, yet changes in PA were also influenced by psychological status. Only patients with major improvements on the ACR/EULAR criteria had significant increase in PA. Accelerometer may serve as an objective tool to define a clinically relevant real-life outcome.

Severe axial and pelvifemoral muscle damage in immune-mediated necrotizing myopathy evaluated by whole-body MRI.

BACKGROUND: Our objective was to define the pattern and severity of muscle damage in immune-mediated necrotizing myopathy (IMNM) and its relationship with clinical and serological features. METHODS: IMNM patients with a whole-body MRI (n=42) were included and compared to sporadic inclusion-body myositis (s-IBM) patients (n=60). Fat replacement was estimated using the Mercuri score in 55 muscles. Overall lesion load was defined as the sum of all abnormal Mercuri scores (reported in % maximal score) and lesion load quotient was defined as the overall lesion load divided by disease duration. Linear relationships between variables were assessed and multidimensional analysis was performed to define homogenous groups of patients. RESULTS: IMNM patients were aged 48.1±15.8 years and had a disease duration of 9.8±8.1 years. Most severely affected muscle groups were located in the pelvifemoral and lumbar region. Unsupervised analysis showed two subgroups of patients: one with mild lesion load (15±10%, n=32/42) and another with severe lesion load (60±10%, n=10/42: p<0.001) associated with a mean disease duration of 6.8±6.0 years and 19.5±5.7 years, respectively (p<0.0001). Correlational studies confirmed that disease duration was the most important predictor of muscle damage. Multivariate analyses demonstrated a more severe involvement in select muscle groups in females and seropositive patients. No difference was found in overall lesion load quotient of IMNM compared to IBM (p=0.07) but with a distinct muscle pattern. CONCLUSION: IMNM is associated with severe axial and pelvifemoral muscle damage. Disease duration is an important predictor of muscle damage. IMNM and s-IBM patients have a comparable damage burden.

Responsiveness to Change of 5-point MRC scale, Endurance and Functional Evaluation for Assessing Myositis in Daily Clinical Practice.

BACKGROUND: Manual muscle testing has been widely used for the evaluation of muscle strength in myositis, yet less attention has been devoted to the evaluation of muscle function and endurance. OBJECTIVE: Our objective was therefore to compare the responsiveness to change of muscle strength, endurance and functional testing following induction therapy for severe myositis flare (requiring high-dose corticosteroids and combined immunotherapy) in patients with a diagnosis of dermatomyositis, immune-mediated necrotizing myopathy, or overlap myositis. METHODS: Muscle status was assessed at baseline and after mean 6.4±1.9 months, using the MRC-5 scale, along with endurance (Barre and Mingazzini maneuvers) and functional evaluation (e.g. chair rise) and responsiveness to change was evaluated using the Standardized Response Mean (SRM) and Standardized Mean Difference. RESULTS: Among the 49 patients included, the strongest responsiveness to change was observed in the muscle testing of the psoas and deltoids (SRM: 1.23 and 1.16, respectively). Noticeably, endurance testing also demonstrated strong responsiveness (SRM: 1.05 and 0.96, respectively), compensating for the poor discriminatory ability of muscle testing and permitting to overcome its ceiling effect. CONCLUSION: Functional and endurance testing provide simple and reliable measures complementing the testing of select proximal muscle groups to evaluate responsiveness to intervention in myositis patients in daily clinical practice. Interest of functional and endurance testing should be evaluated prospectively as outcome measures in myositis clinical trials.

Rituximab in the Treatment of Refractory Anti-HMGCR Immune-mediated Necrotizing Myopathy.

OBJECTIVE: A pathogenic role of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies has been proposed. Our objective was to assess efficacy of rituximab (RTX) in anti-HMGCR immune-mediated necrotizing myopathy. METHODS: All patients who had been treated with RTX were retrospectively reviewed to assess features and outcome. RESULTS: Three of 9 patients demonstrated stable or improved muscle strength ± decline in creatine kinase levels, or T2/short-tau inversion recovery hypersignal decrease on magnetic resonance imaging following RTX treatment. RTX permitted intravenous immunoglobulin discontinuation and corticosteroid reduction to low dose in 2 patients. CONCLUSION: One-third of patients with refractory anti-HMGCR had improved strength or other evidence of improved disease activity following RTX treatment.