Urinary methotrexate dosage in rheumatoid arthritis, in patients treated for at least 6 months: a potential marker of adherence.

OBJECTIVES: Non-adherence to rheumatoid arthritis (RA) treatments must be identified. A methotrexate (MTX) urinary dosage (METU) was recently developed. The aim of our study was to assess adherence to MTX in RA using METU in real-life conditions and to compare it with indirect adherence measurement technics. METHODS: We performed a cross-sectional study at Reims University Hospital. We included over 18-year-old patients with RA treated by MTX for more than 6 months. Patients were invited to complete demographic, clinical and psychological questionnaires and adherence measurement technics (Compliance Questionnaire of Rheumatology (CQR) and Medication Possession Ratio (MPR)). A urinary sample was collected to measure MTX and information about tolerance was evaluated through Methotrexate Intolerance Severity Score. RESULTS: 84 patients were included, 26 using oral MTX, 58 subcutaneous (SC) MTX. Among them, 73% were female, mean age was 61.5 years, MTX mean dose was 15 mg/week and 61.9% were treated by biological DMARDs (Disease Modifying Antirheumatic Drugs). 77 patients (91.7%) were adherent to treatment according to METU, whereas MPR and CQR reported less adherence (69.5% and 61.9%, respectively). MPR and METU were not significantly different in SC MTX users (p=0.059). Non-adherent patients had a higher number of tender joints and C reactive protein value (p<0.05). CONCLUSION: This is the first largest study evaluating MTX adherence in patients with RA using a urinary dosage. We identified that indirect adherence measurements did not reflect real-life adherence. It would be appreciable to realise METU, in a new study, in patients with RA with unexplained response to treatment, to consider it before escalating therapeutic strategy.

Myostatin in idiopathic inflammatory myopathies: Serum assessment and disease activity.

AIMS: In idiopathic inflammatory myopathies (IIM), disease activity is difficult to assess, and IIM may induce severe muscle damage, especially in immune-mediated necrotising myopathies (IMNM) and inclusion body myositis (IBM). We hypothesise that myostatin, a negative regulator of muscle mass, could be a new biomarker of disease activity and/or muscle damage. METHODS: Prospective assessment of myostatin protein level in 447 IIM serum samples (dermatomyositis [DM], n = 157; IBM, n = 72; IMNM, n = 125; and antisynthetase syndrome [ASyS], n = 93) and 59 healthy donors (HD) was performed by ELISA. A gene transcript analysis was also carried out on 18 IIM muscle biopsies and six controls to analyse myostatin and myostatin pathway-related gene expression. RESULTS: IIM patients had lower myostatin circulating protein levels and gene expression compared to HD (2379 [1490; 3678] pg/ml vs 4281 [3169; 5787] pg/ml; p < 0.0001 and log2FC = -1.83; p = 0.0005, respectively). Myostatin-related gene expression varied accordingly. Based on the Physician Global Assessment, inactive IIM patients showed higher myostatin levels than active ones. This was the case for all IIM subgroups, except IMNM where low myostatin levels were maintained (2186 [1235; 3815] vs 2349 [1518; 3922] pg/ml; p = 0.4). CONCLUSIONS: Myostatin protein and RNA levels are decreased in all IIM patients, and protein levels correlate with disease activity. Inactive ASyS and DM patients have higher myostatin levels than active patients. Myostatin could be a marker of disease activity in these subgroups. However, IMNM patients do not have significant increase in myostatin levels after disease remission. This may highlight a new pathological disease mechanism in IMNM patients.

Cluster analysis unveils a severe persistent respiratory impairment phenotype 3-months after severe COVID-19.

BACKGROUND: The mid-term respiratory sequelae in survivors of severe COVID-19 appear highly heterogeneous. In addition, factors associated with respiratory sequelae are not known. In this monocentric prospective study, we performed a multidisciplinary assessment for respiratory and muscular impairment and psychological distress 3 months after severe COVID-19. We analysed factors associated with severe persistent respiratory impairment, amongst demographic, COVID-19 severity, and 3-month assessment. METHODS: Patients with severe SARS-CoV-2 pneumonia requiring ≥ 4L/min were included for a systematic 3-month visit, including respiratory assessment (symptoms, lung function, CT scan), muscular evaluation (body composition, physical function and activity, disability), psychopathological evaluation (anxiety, depression, post-traumatic stress disorder-PTSD) and quality of life. A cluster analysis was performed to identify subgroups of patients based on objective functional measurements: DLCO, total lung capacity and 6-min walking distance (6MWD). RESULTS: Sixty-two patients were analysed, 39% had dyspnea on exercise (mMRC ≥ 2), 72% had DLCO < 80%, 90% had CT-scan abnormalities; 40% had sarcopenia/pre-sarcopenia and 31% had symptoms of PTSD. Cluster analysis identified a group of patients (n = 18, 30.5%) with a severe persistent (SP) respiratory impairment (DLCO 48 ± 12%, 6MWD 299 ± 141 m). This SP cluster was characterized by older age, severe respiratory symptoms, but also sarcopenia/pre-sarcopenia, symptoms of PTSD and markedly impaired quality of life. It was not associated with initial COVID-19 severity or management. CONCLUSIONS AND CLINICAL IMPLICATION: We identified a phenotype of patients with severe persistent respiratory and muscular impairment and psychological distress 3 months after severe COVID-19. Our results highlight the need for multidisciplinary assessment and management after severe SARS-CoV-2 pneumonia. Trial registration The study was registered on ClinicalTrials.gov (May 6, 2020): NCT04376840.

Association between obesity-related dyspnea in daily living, lung function and body composition analyzed by DXA: a prospective study of 130 patients.

BACKGROUND: Obesity is a risk factor for dyspnea. However, investigations of daily living obesity-related dyspnea are limited and its mechanisms remain unclear. We conducted a cross-sectional study to analyze the relationships between dyspnea in daily living, lung function, and body composition in patients with obesity. METHODS: One-hundred and thirty patients (103 women/27 men), candidate for bariatric surgery, with a mean ± SD Body Mass Index (BMI) of 44.8 ± 6.8 kg/m2 were included. Dyspnea was assessed by the modified Medical Research Council (mMRC) scale. Comorbidities, laboratory parameters, pulmonary function tests, arterial blood gases, six-minute walk test (6MWT), handgrip strength, and DXA body composition were analyzed. RESULTS: Thirty-one percent of patients exhibited disabling dyspnea in daily living (mMRC ≥ 2). Compared with patients without disabling dyspnea (mMRC < 2), significant dyspnea (mMRC ≥ 2) was associated with a lower 6MWT distance (395 ± 103 m vs 457 ± 73 m, p < 0.001), lower lung volumes including Expiratory Reserve Volume (42 ± 28% vs 54 ± 27%, p = 0.024), Vital Capacity (95 ± 14 vs 106 ± 15%, p < 0.001) and Forced expiratory volume in one second (95 ± 13 vs 105 ± 15%, p = 0.002), a higher BMI (48.2 ± 7.7 vs 43.2 ± 5.7 kg/m2, p = 0.001) and a higher percentage of fat mass in the trunk (46 ± 5 vs 44 ± 5 p = 0.012) and android region (52 ± 4 vs 51 ± 4%, p = 0.024). There was no difference regarding comorbidities (except hypertension), laboratory parameters, and sarcopenia markers between patients with (mMRC ≥ 2) and without (mMRC < 2) disabling dyspnea. CONCLUSION: Dyspnea in patients with obesity is associated with a reduction in lung volumes and a higher percentage of fat mass in central body regions. How dyspnea and body composition may change with interventions like physical activity or bariatric surgery remains to be investigated.

The role of interferons type I, II and III in myositis: A review.

The classification of idiopathic inflammatory myopathies (IIM) is based on clinical, serological and histological criteria. The identification of myositis-specific antibodies has helped to define more homogeneous groups of myositis into four dominant subsets: dermatomyositis (DM), antisynthetase syndrome (ASyS), sporadic inclusion body myositis (sIBM) and immune-mediated necrotising myopathy (IMNM). sIBM and IMNM patients present predominantly with muscle involvement, whereas DM and ASyS patients present additionally with other extramuscular features, such as skin, lung and joints manifestations. Moreover, the pathophysiological mechanisms are distinct between each myositis subsets. Recently, interferon (IFN) pathways have been identified as key players implicated in the pathophysiology of myositis. In DM, the key role of IFN, especially type I IFN, has been supported by the identification of an IFN signature in muscle, blood and skin of DM patients. In addition, DM-specific antibodies are targeting antigens involved in the IFN signalling pathways. The pathogenicity of type I IFN has been demonstrated by the identification of mutations in the IFN pathways leading to genetic diseases, the monogenic interferonopathies. This constitutive activation of IFN signalling pathways induces systemic manifestations such as interstitial lung disease, myositis and skin rashes. Since DM patients share similar features in the context of an acquired activation of the IFN signalling pathways, we may extend underlying concepts of monogenic diseases to acquired interferonopathy such as DM. Conversely, in ASyS, available data suggest a role of type II IFN in blood, muscle and lung. Indeed, transcriptomic analyses highlighted a type II IFN gene expression in ASyS muscle tissue. In sIBM, type II IFN appears to be an important cytokine involved in muscle inflammation mechanisms and potentially linked to myodegenerative features. For IMNM, currently published data are scarce, suggesting a minor implication of type II IFN. This review highlights the involvement of different IFN subtypes and their specific molecular mechanisms in each myositis subset.

[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.

CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis.

BACKGROUND: Myositis is a heterogeneous group of muscular auto-immune diseases with clinical and pathological criteria that allow the classification of patients into different sub-groups. Inclusion body myositis is the most frequent myositis above fifty years of age. Diagnosing inclusion body myositis requires expertise and is challenging. Little is known concerning the pathogenic mechanisms of this disease in which conventional suppressive-immune therapies are inefficacious. OBJECTIVES: Our aim was to deepen our understanding of the immune mechanisms involved in inclusion body myositis and identify specific biomarkers. METHODS: Using a panel of thirty-six markers and mass cytometry, we performed deep immune profiling of peripheral blood cells from inclusion body myositis patients and healthy donors, divided into two cohorts: test and validation cohorts. Potential biomarkers were compared to myositis controls (anti-Jo1-, anti-3-hydroxyl-3-methylglutaryl CoA reductase-, and anti-signal recognition particle-positive patients). RESULTS: Unsupervised analyses revealed substantial changes only within CD8+ cells. We observed an increase in the frequency of CD8+ cells that expressed high levels of T-bet, and containing mainly both effector and terminally differentiated memory cells. The senescent marker CD57 was overexpressed in CD8+T-bet+ cells of inclusion body myositis patients. As expected, senescent CD8+T-bet+ CD57+ cells of both patients and healthy donors were CD28nullCD27nullCD127null. Surprisingly, non-senescent CD8+T-bet+ CD57- cells in inclusion body myositis patients expressed lower levels of CD28, CD27, and CD127, and expressed higher levels of CD38 and HLA-DR compared to healthy donors. Using classification and regression trees alongside receiver operating characteristics curves, we identified and validated a frequency of CD8+T-bet+ cells >51.5% as a diagnostic biomarker specific to inclusion body myositis, compared to myositis control patients, with a sensitivity of 94.4%, a specificity of 88.5%, and an area under the curve of 0.97. CONCLUSION: Using a panel of thirty-six markers by mass cytometry, we identify an activated cell population (CD8+T-bet+ CD57- CD28lowCD27lowCD127low CD38+ HLA-DR+) which could play a role in the physiopathology of inclusion body myositis, and identify CD8+T-bet+ cells as a predominant biomarker of this disease.

Autoantibodies Associated With Connective Tissue Diseases: What Meaning for Clinicians?

Connective tissue diseases (CTDs) such as systemic lupus erythematosus, systemic sclerosis, myositis, Sjögren's syndrome, and rheumatoid arthritis are systemic diseases which are often associated with a challenge in diagnosis. Autoantibodies (AAbs) can be detected in these diseases and help clinicians in their diagnosis. Actually, pathophysiology of these diseases is associated with the presence of antinuclear antibodies. In the last decades, many new antibodies were discovered, but their implication in pathogenesis of CTDs remains unclear. Furthermore, the classification of these AAbs is nowadays misused, as their targets can be localized outside of the nuclear compartment. Interestingly, in most cases, each antibody is associated with a specific phenotype in CTDs and therefore help in better defining either the disease subtypes or diseases activity and outcome. Because of recent progresses in their detection and in the comprehension of their pathogenesis implication in CTD-associated antibodies, clinicians should pay attention to the presence of these different AAbs to improve patient's management. In this review, we propose to focus on the different phenotypes and features associated with each autoantibody used in clinical practice in those CTDs.