Juvenile dermatomyositis with Anti-SAE antibodies in a Moroccan child associated with pseudo-angioedema: a case report.

BACKGROUND: Juvenile Dermatomyositis (JDM) is the leading cause of non-infectious inflammatory myopathy in children. It is a heterogeneous group of autoimmune diseases characterized by a variable combination of muscular, dermatological, and visceral involvement. Myositis-specific autoantibodies help define homogeneous subgroups with common clinical characteristics and prognoses. Anti-SAE (small ubiquitin-like modifier 1 (SUMO-1) activating enzyme) antibodies are among the most recently discovered specific autoantibodies. The presence of these antibodies is very rare, making it challenging to define clinical features and prognosis in the juvenile form. We report the first case of an African patient with juvenile dermatomyositis and positive anti-SAE antibodies. CASE REPORT: A 5-year-3-month-old Moroccan boy presented to the pediatric emergency department with dysphagia that had been evolving for two days, preceded two months earlier by facial erythema associated with fatigue, lower limb pain, difficulty walking, and progressive inflammatory polyarthralgia. On admission, the child had a heliotrope rash with predominant pseudo-angioedema on the lips, periungual telangiectasia, and Gottron's papules over the bilateral interphalangeal and metatarsophalangeal joints. The patient had a more pronounced proximal muscle weakness in the lower limbs. He had no urticaria, fever, arthritis, calcinosis, cutaneous ulcers, or lipodystrophy. The Joint examination was normal, as was the pleuropulmonary examination. The electroneuromyography showed myogenic changes in all four limbs. Laboratory findings showed elevated levels of creatine phosphokinase and lactate dehydrogenase and a mild inflammatory syndrome. The electrocardiogram was normal. The anti-SAE antibodies were positive. The boy was diagnosed with juvenile dermatomyositis. He received methylprednisolone bolus therapy followed by oral prednisone. The latter was gradually tapered in combination with weekly intramuscular methotrexate. As a result, dysphagia disappeared within 48 h. After two weeks, there was an improvement in the muscular score and a significant regression of facial pseudo-angioedema. CONCLUSION: We report the first African patient with anti-SAE autoantibody-positive JDM. He had a typical dermatological manifestation of JDM associated with pseudo-angioedema predominant on the lips; a rarely reported sign in DM and JDM patients. The patient responded well to corticosteroid therapy and methotrexate.

[Dermatomyositis: new antibody, new classification]. / Dermatomyosites Nouveaux anticorps, nouvelle classification.

Dermatomyositis are rare chronic auto-immune diseases characterized by cutaneous involvement. Diagnosis could be made in childhood or in aldult. There are some different clinical and histological presentation associated with different myositis specific antibody. There are five dermatomyositis specific autoantibodies, anti-Mi2, anti-Tif1-γ, anti-NXP2, anti-MDA5, and anti-SAE. Anti-Mi2 are associated with "classical form" of DM with cutaneous and muscular involvement. Anti-Tif1γ and anti-NXP2 are found in juvenile and adult dermatomyositis, and are associated with recurrent diseases with cutaneous involvement at the forefront. In adults, they are associated with cancer. Anti-MDA5 antibodies are associated with a systemic involvement and an interstitial lung disease. Finally, anti-SAE have been found only in adults, with a classic form.

TITLE: Dermatomyosites Nouveaux anticorps, nouvelle classification. ABSTRACT: Les dermatomyosites (DM) sont des maladies auto-immunes rares du groupe des myopathies inflammatoires idiopathiques, définies par une atteinte cutanée caractéristique. Elles peuvent survenir dans l'enfance, ou chez l'adulte. Il existe des variations phénotypiques entre les DM concernant la présentation cutanéomusculaire (ex: amyopathique) mais aussi la présentation extra-cutanéomusculaire (ex: atteinte pulmonaire ou articulaire associée). Le caractère auto-immun de ces pathologies est souligné dans 60 % des cas par la présence d'anticorps spécifique de myosite. Ces derniers sont associés à la présence de caractéristiques cliniques, histologiques, mais aussi pronostiques. Ils sont au nombre de cinq, les anti-Mi2, anti-Tif1-γ, anti-NXP2, anti-MDA5 et anti-SAE. Les anti-Mi2 sont associées à une forme clinique cutanée classique, une atteinte musculaire souvent sévère au diagnostic et une bonne évolution sous traitement. Les deux suivants, fréquents chez l'enfant et l'adulte, sont associés à des formes récidivantes cutanées et sont fortement associés aux cancers chez l'adulte. Les anti-MDA5 sont les anticorps associés aux formes les plus systémiques avec une atteinte pulmonaire interstitielle rapidement progressive pouvant être très grave. Enfin, les anti-SAE n'ont été décrits que chez l'adulte, avec une atteinte classique.

Neddylation inhibition upregulates PD-L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma.

Pevonedistat (MLN4924), a specific NEDD8-activating enzyme inhibitor, has been considered as a promising treatment for glioblastoma, which is currently in Phase I/II clinical trials. On the other hand, inhibition of neddylation pathway substantially upregulates the expression of T cell negative regulator programmed death-ligand 1 (PD-L1), which might account for the potential resistance via evasion of immune surveillance checkpoints. Whether administration of anti-PD-L1 enhances the efficacy of pevonedistat through a cytotoxic T cell-dependent mechanism in glioblastoma needs to be investigated. Here, we report that depletion of neddylation pathway key enzymes markedly elevates PD-L1 expression in glioblastoma cancer cells. Consistently, neddylation inhibitor pevonedistat significantly enhances PD-L1 expression in both glioblastoma cancer cell lines and animal models. Mechanistically, pevonedistat increases PD-L1 mRNA levels mainly through inhibiting Cullin1-F-box and WD repeat domain-containing 7 E3 ligase activity and accumulating c-MYC proteins, a direct transcriptional activator of PD-L1 gene expression. In addition, inhibition of Cullin3 activity by pevonedistat also blocks PD-L1 protein degradation. Importantly, pevonedistat attenuates T cell killing through PD-L1 induction, and blockade of PD-L1 restores the sensitivity of pevonedistat-treated glioblastoma cancer cells to T cell killing. The combination of pevonedistat and anti-PD-L1 therapy compared to each agent alone significantly increased the therapeutic efficacy in vivo. Our study demonstrates inhibition of neddylation pathway suppresses cancer-associated immunity and provides solid evidence to support the combination of pevonedistat and PD-L1/programmed cell death protein 1 immune checkpoint blockade as a potential therapeutic strategy to treat glioblastoma.

Diffuse pruritic erythema as a clinical manifestation in anti-SAE antibody-associated dermatomyositis: a case report and literature review.

Anti-small ubiquitin-like modifier-1 activating enzyme (anti-SAE) antibodies have been recently discovered especially for myosin and identified as dermatomyositis (DM) marker. The frequency of anti-SAE antibodies in DM patients is extremely low. Diffuse pruritic erythema may be one kind of clinical manifestations of DM with anti-SAE antibodies. In this report, a 48-year-old female patient with amyopathic dermatomyositis (ADM) carrying anti-SAE antibodies presented diffuse pruritic erythema for 5 months. Diffuse pruritic erythema improved after treatment with prednisolone, cyclosporine, and thalidomide. The clinical characteristics of 75 previously reported cases with anti-SAE antibody-positive DM were reviewed, and the manifestations of the Asian and Western cohorts were compared. It was revealed that the Asian patients were more susceptible to diffuse erythema (17/34 vs. 3/41, P = 0.000), dysphagia (16/34 vs. 10/41, P = 0.040), and interstitial lung disease (ILD) (21/34 vs. 5/41, P = 0.000) compared with the Western patients. The frequency of malignancy in the Asian cohort was significantly higher than that in the Western cohort (10/34 vs. 4/41, P = 0.030).

[Retrospective analysis of anti-TIF1gamma, anti-NXP2 and anti-SAE1/2 antibodies carriers at Bordeaux university hospital from November 2014 to February 2017]. / Analyse rétrospective des patients porteurs d'anticorps anti-TIF1gamma, anti-NXP2 et anti-SAE1/2 au CHU de Bordeaux de novembre 2014 à février 2017.

INTRODUCTION: Dermatomyositis are rare autoimmune diseases. The discovery of specific antibodies such as the anti-TIF1γ, anti-SAE1/2 and anti-NXP2 antibodies has been associated with specific clinical phenotypes. The recent development of standardized kits based on immunodot method is a progress in dermatomyositis diagnosis. Here, we report the clinical characteristics of patients carrying these antibodies with or without clinical setting of dermatomyositis. METHODS: This single-center french retrospective study was conducted from November 2014 to February 2017 at Bordeaux university hospital. Patients carrying anti-TIF1γ, anti-SAE1/2 and anti-NXP2 antibodies, detected by immunodot, were included. RESULTS: Among the 58 patients included, only 10 were finally diagnosed with dermatomyositis. Some form of cancer was found in all anti-TIF1γ antibodies positive patients associated with dermatomyositis. Among the 48 anti-TIF1γ, anti-SAE1/2 and anti-NXP2 antibodies positive patients without clinical phenotype of dermatomyositis, 30 had autoimmune or inflammatory condition and 39 patients presented a significant biological autoimmunity. None of them developed dermatomyositis during the follow-up. CONCLUSION: The immunodot kit allowed the diagnosis of 10 dermatomyositis. A high number of autoantibody positive patients without dermatomyositis raises the issue of the immunodot's performances in the context of biological autoimmunity.

Association Between Autoantibody Phenotype and Cutaneous Adverse Reactions to Hydroxychloroquine in Dermatomyositis.

Importance: Hydroxychloroquine sulfate is a commonly used medication for patients with dermatomyositis and has been associated with a uniquely elevated risk of adverse cutaneous reactions in this population. No studies to date have examined whether certain subsets of patients with dermatomyositis are at increased risk of experiencing a hydroxychloroquine-associated skin eruption. Objective: To identify disease features that increase the risk of hydroxychloroquine-associated skin eruption in adults with dermatomyositis. Design, Setting, and Participants: A retrospective cohort study was conducted in the outpatient dermatology clinic at a tertiary academic referral center. All adults with dermatomyositis (age >18 years) who started receiving hydroxychloroquine between July 1, 1990, and September 13, 2016, were eligible for the analysis. Patients were considered to have a hydroxychloroquine-associated skin eruption if a skin eruption had developed within their first 4 weeks of treatment and resolved with discontinuation of hydroxychloroquine therapy. Exposures: One or more doses of hydroxychloroquine. Main Outcomes and Measures: The associations between autoantibodies (against transcription intermediary factor 1γ [TIF-1γ], nucleosome-remodeling deacetylase complex [Mi-2], nuclear matrix protein [NXP-2], small ubiquitinlike modifier 1 activating enzyme [SAE-1/2], melanoma differentiation-associated gene 5 [MDA-5], histidyl-transfer RNA synthetase [Jo-1], Ku, and signal recognition particles) and cutaneous adverse reactions to hydroxychloroquine in patients with dermatomyositis. Results: A total of 111 patients met the inclusion criteria, and 23 (20.7%) developed a hydroxychloroquine-associated skin eruption (20 [87.0%] were women with a mean [SD] age of 49 [14] years at diagnosis). Skin eruptions were approximately 3 times more common in patients with anti-SAE-1/2 autoantibodies (7 of 14 [50.0%]) compared with those without the autoantibody (16 of 97 [16.5%]). In contrast, none of 15 patients with anti-MDA-5 autoantibodies had a skin eruption vs 23 of 96 (24.0%) of those without the autoantibody. In exact logistic regressions adjusted for age, race/ethnicity, sex, amyopathic status, anti-Ro52 status, and dermatomyositis-associated cancer, the presence of anti-SAE-1/2 autoantibodies was significantly associated with a hydroxychloroquine-associated skin eruption (odds ratio [OR], 8.43; 95% CI, 1.98-49.19; P = .003) and presence of anti-MDA-5 autoantibodies was significantly negatively associated with a hydroxychloroquine-associated skin eruption (OR, 0.06; 95% CI, 0.0004-0.52; P = .006). No other autoantibodies were significantly positively or negatively associated with a hydroxychloroquine-associated skin eruption. Conclusions and Relevance: Adverse skin reactions to hydroxychloroquine are relatively common in a US cohort of patients with dermatomyositis. Our data suggest that pathophysiologic differences exist between autoantibody subsets in dermatomyositis.

Clinical significance of autoantibodies in dermatomyositis and systemic sclerosis.

Autoimmune connective tissue diseases, including dermatomyositis and systemic sclerosis, have a heterogeneous clinical presentation and prognosis; moreover, their clinical features are often incomplete and overlap with other rheumatic disorders, which can make diagnosis and prognostic stratification challenging. Specific autoantibodies have been associated with certain clinical findings as well as prognostic implications, and many new associations have been made over the last decade. Although patient populations manifest considerable heterogeneity, autoantibodies can be used to help predict clinical features, prognosis, and response to therapy. In this review, the clinical and prognostic implications associated with disease-specific autoantibodies in dermatomyositis and scleroderma are summarized with an emphasis on how the clinician can use this information for patient care.

Molecular cloning and characterization of Aos1 and Uba2 from the orange-spotted grouper (Epinephelus coioides).

Small ubiquitin-related modifiers (SUMOs) are post-translationally conjugated to other proteins and are essential regulators of a wide range of cellular processes. Covalent attachment of SUMO requires an enzymatic cascade consisting of a single E1-activating enzyme (Aos1 and Uba2 heterodimer), a single E2-conjugating enzyme (Ubc9), and one of several E3 ligases that facilitate transfer of SUMO from Ubc9 to the substrate. In the present study, the Aos1 and Uba2 homologues (EcAos1 and EcUba2) from the orange-spotted grouper (Epinephelus coioides) were cloned and their possible roles in fish immunity were analyzed. The open reading frame (ORF) of EcAos1 contains 1050 base pairs (bp) encoding a 350 amino acid protein with a predicted molecular mass of 38.97 kDa EcAos1 has a nuclear localization signal (NLS) at residues 193-203. The ORF of EcUba2 contains 1950 bp encoding a 650 amino acid protein with a predicted molecular mass of 71.3 kDa EcUba2 has a NLS at residues 608-630. Quantitative real-time polymerase chain reaction analysis indicated that both EcAos1 and EcUba2 were distributed in all examined tissues. The expression levels of EcAos1 and EcUba2 in the spleen and head kidney of E. coioides were differentially up-regulated when challenged with polyinosine-polycytidylic acid. Green fluorescence of both pEGFP-C1-EcAos1 and pEGFP-C1-EcUba2 was distributed in the nucleus of GS cells. When the NLSs of EcAos1 and EcUba2 were deleted, the cellular localizations all changed. Over-expression of EcAos1 and EcUba2 inhibited red-spotted grouper nervous necrosis virus infection and replication. These results are important for better understanding of the SUMO pathway in fish and provide insights into the regulatory mechanism of viral infection in E. coioides under farmed conditions.

[A case of Hashimoto's encephalopathy successfully treated with cyclophosphamide pulse therapy].

Hashimoto's encephalopathy has been described as an autoimmune disorder which demonstrates favorable response to corticosteroid therapy. However, steroid-resistant cases which require additional treatment are frequently reported, and there is no consensus how such cases should be treated. We present a 69 years-old man, who progressed cognitive dysfunction in the past three months. Anti-thyroid and anti-NH2 terminal of alpha-enolase antibodies were positive. Because initial corticosteroid therapy was ineffective, cyclophosphamide (CPA) pulse therapy was added, and his cognitive function was immediately improved. He had no relapse after tapering dose of corticosteroid for three years. CPA pulse therapy should be considered for steroid-resistant Hashimoto's encephalopathy.

Antibodies to small ubiquitin-like modifier activating enzyme are associated with a diagnosis of dermatomyositis: results from an unselected cohort.

The aim of this study was to examine the frequency and significance of antibodies targeting the small ubiquitin-like modifier 1 activating enzyme (SAE) in patients under serologic evaluation for idiopathic inflammatory myopathies. Patient sera (n = 17) recognizing bands at approximately 40 (SAE1) and 90 (SAE2) kDa were identified in 6445 consecutive samples for myositis autoantibody evaluation by immunoprecipitation (IP) of S35-labeled K562 cell lysate. All 17 positive samples, 176 disease, and 67 healthy controls were evaluated for SAE1 antibodies using a line immunoblot assay (LIA). Clinical data of SAE antibody-positive patients were obtained by retrospective chart review. Positivity with both methods was associated with a diagnosis dermatomyositis with characteristic skin manifestations of varying severity and muscle involvement. Majority of the patients were female (73.7%), mean age of 55.0 (range 12.0-82.0) years at the time of testing. Using the IP as reference, the SAE1 LIA had a sensitivity of 100% (95% CI 82.4-100%), specificity of 99.6% (95% CI 97.7-100%), positive predictive value of 95.0% (95% CI 75.1-99.9%), and negative predictive value of 100% (95% CI 98.5-100%). This study confirms the association of SAE antibodies in patients with dermatomyositis. A combination of IP and the LIA specific for SAE1 may be useful in antibody detection.

[Dermatomyositis and Autoantibodies].

Recent studies have identified novel dermatomyositis-specific autoantibodies and revealed that disease-specific autoantibodies become positive at a high rate in this disease. Moreover, these autoantibodies have been demonstrated to show a strong correlation with distinct clinical manifestations and complications such as interstitial lung disease and malignancy. Thus, these autoantibodies are now recognized as useful tools to classify this varied disease into more homogeneous subsets. In this review, the clinical significance of five dermatomyositis-specific autoantibodies, anti-Mi-2, anti-MDA5, anti-TIF1, anti-NXP2, and anti-SAE, was described.

Dermatomyositis Clinical and Pathological Phenotypes Associated with Myositis-Specific Autoantibodies.

PURPOSE OF REVIEW: Dermatomyositis is an idiopathic inflammatory myopathy with a variety of systemic and cutaneous manifestations. The myositis-specific autoantibodies (MSAs) are associated with phenotypic features and provide a tool for sub-classification of dermatomyositis patients. This review focuses on recent work characterizing the clinical features that accompany the MSAs in dermatomyositis. RECENT FINDINGS: There is increasing recognition of the distinct clinical and pathological phenotypes associated with each MSA. Most of these features display considerable overlap between MSA groups. Despite this, there are notable differences between the typical combinations of cutaneous and systemic manifestations, response to therapy, prognosis, and disease sequelae that define each dermatomyositis MSA group. The MSAs may ultimately improve diagnosis and sub-classification of dermatomyositis patients. However, more work is needed to understand the pathologic basis for much of the heterogeneity found within these subgroups.

Prevalence of Myositis-Specific Antibodies in Idiopathic Interstitial Pneumonias.

Although included in the serological domain of the 'interstitial pneumonia with auto-immune features' (IPAF) research statement, the search for myositis-specific antibodies (MSA) is not incorporated in routine clinical practice. The objective of the study was to evaluate MSA prevalence in an idiopathic interstitial pneumonia (IIP) cohort (n = 68) with suggestive morphological interstitial lung disease patterns. Twelve of 68 patients (17.6%) carried MSA, whereof only two were anti-nuclear antibody-positive. Besides female gender, no demographic or pulmonary function parameter was predictive for MSA positivity. MSA were present in 32.4% of IPAF patients (n = 37), being essential for IPAF diagnosis in four of them (10.8%).

Altered Expression Patterns of the Sumoylation Enzymes E1, E2 and E3 Are Associated with Glucose Oxidase- and UVA-Induced Cataractogenesis.

PURPOSE: Protein sumoylation is a well established regulatory mechanism that regulates chromatin structure and dynamics, cell proliferation and differentiation, stress response and cell apoptosis. In the vertebrate eye, we and others have shown that sumoylation plays an indispensable role in regulating eye development. During stress induction and aging process, the ocular tissues gradually loss their normality and develop major ocular diseases such as cataract and aging-related macular degeneration. We have recently demonstrated that sumoylation actively regulates differentiation of lens cells, whether this process is implicated in lens pathogenesis remains to be investigated. In this study, we have demonstrated that transparent mouse lenses treated with glucose oxidase and UVA irradiation undergo in vitro cataract formation, and associated with this process, the expression patterns of the 3 sumoylation enzymes have been found significantly altered. METHODS: Four-week-old C57BL/6J mice were used in our experiment. Lenses were carefully excised from eyes and cultured in M199 medium (Sigma 3769) for at least 12 hours. Transparent lenses (without surgical damage) were selected for experimentation. The lenses were exposed to UVA for 60 min or treated with 30 mU/mL glucose oxidase (GO, MP Biomedicals, 1673) to induce cataract formation. The mRNA levels were analysed with qRT-PCR. The protein levels were determined with western blot analysis and quantitated with Image J. RESULTS: we have obtained the following results: 1) Both GO treatment and UVA irradiation can induce cataract formation in the in vitro cultured mouse lenses; 2) With GO treatment, the mRNAs and proteins for the 5 sumoylation enzymes were all significantly downregulated; 3) With UVA irradiation, the changes in the expression patterns of the mRNAs and proteins for the SAE1, UBA2 , UBC9 and PIAS1 were opposite, while the mRNAs were upregulated either significantly (for SAE1, UBA2 and UBC9) or slightly (PIAS1), the proteins for all 4 sumoylation enzymes were downregulated; For RanBP2, the UVA induced changes in both mRNA and protein are consist with the GO treatment. CONCLUSION: Under GO and UVA irradiation conditions, the expression levels of both mRNA and protein for the three major sumoylation enzymes were significantly changed. Our results suggest that altered expression patterns of the sumoylation enzymes are associated with oxidative stressinduced cataractogenesis.