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Journal of Medicinal Chemistry Jun 2024Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association...
Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).
Topics: Humans; Animals; TYK2 Kinase; Protein Kinase Inhibitors; Mice; Autoimmune Diseases; Adenosine Triphosphate; Psoriasis; Female; Drug Discovery; Male; Lupus Erythematosus, Systemic; Structure-Activity Relationship; Adult
PubMed: 38805213
DOI: 10.1021/acs.jmedchem.4c00769 -
Journal of Inflammation Research 2024To investigate the prevalence, risk factors and prognosis of invasive pulmonary aspergillosis (IPA) in patients with anti-melanoma differentiation-associated gene 5...
OBJECTIVE
To investigate the prevalence, risk factors and prognosis of invasive pulmonary aspergillosis (IPA) in patients with anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+ DM).
METHODS
A retrospective analysis was conducted in anti-MDA5+ DM patients diagnosed between January 2016 and March 2023. Patients with lower respiratory tract specimens were categorized into IPA+ and IPA- groups based on the presence of IPA and their clinical characteristics and prognoses then compared.
RESULTS
Of the 415 patients diagnosed with anti-MDA5+ DM, 28 cases had IPA (prevalence rate of 6.7%) with being the most common species. The patients were categorized into IPA+ (n=28) and IPA- (n=98) groups, with no significant age or gender-related differences (>0.05). The IPA+ group had a lower lymphocyte count, particularly the CD4+ T-cell count, and reduced serum albumin and higher serum ferritin levels ( all<0.05). An elevated bronchoalveolar lavage fluid (BALF) galactomannan level was found to be the sole independent risk factor for the occurrence of IPA (adjusted OR=2.191, =0.029) with a cut-off value of 0.585 and area under the curve of 0.779. The mortality rate in the IPA+ group was 25%. Compared to survivors, non-survivors in this group exhibited a higher incidence of rapidly progressive interstitial lung disease, lower lymphocyte counts, and increased co-infection with ( all<0.05).
CONCLUSION
IPA was not rare in patients with anti-MDA5+ DM, with elevated BALF galactomannan levels being an independent risk factor for IPA occurrence. Clinicians must exercise vigilance to identify patients exhibiting the aforementioned risk factors.
PubMed: 38800596
DOI: 10.2147/JIR.S460702 -
Journal of Autoimmunity May 2024- Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi...
OBJECTIVES
- Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment.
METHODS
- We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology.
RESULTS
- 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment.
CONCLUSION
- JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.
PubMed: 38797048
DOI: 10.1016/j.jaut.2024.103248 -
Journal of Autoimmunity May 2024To investigate the epigenetic footprint of idiopathic inflammatory myopathies (IIM) through characterization of circulating extracellular vesicles (EVs) and the...
OBJECTIVE
To investigate the epigenetic footprint of idiopathic inflammatory myopathies (IIM) through characterization of circulating extracellular vesicles (EVs) and the expression of EV-derived small non-coding RNAs (sncRNAs).
METHODS
In this cross-sectional study, EVs were isolated by size-exclusion chromatography from plasma of patients with IIM and age- and sex-matched healthy donors (HD). EV-derived sncRNAs were sequenced and quantified using Next-Generation Sequencing (NGS). Following quality control and normalization, filtered count reads were used for differential microRNA (miRNA) and piwi-interacting RNA (piRNA) expression analyses. Putative gene targets enriched for pathways implicated in IIM were analyzed. Patients' clinical and laboratory characteristics at the time of sampling were recorded.
RESULTS
Forty-seven IIM patients and 45 HD were enrolled. MiR-486-5p (p < 0.01), miR-122-5p, miR-192-5p, and miR-32-5p were significantly upregulated (p < 0.05 for all), while miR-142-3p (p < 0.001), miR-141-3p (p < 0.01), let-7a-5p (p < 0.05) and miR-3613-5p (p < 0.05) downregulated in EVs from IIM patients versus HD. MiR-486-5p was associated with raised muscle enzymes levels. Several target genes of up/downregulated miRNAs in IIM participate in inflammation, necroptosis, interferon and immune signaling. Six piRNAs were significantly dysregulated in IIM EVs versus HD (p < 0.05). Within IIM, miR-335-5p was selectively upregulated and miR-27a-5p downregulated in dermatomyositis (n = 21, p < 0.01). Finally, plasma EV levels were significantly increased in cancer-associated myositis (CAM, n = 12) versus non-CAM IIM (n = 35, p = 0.02) and HD (p < 0.01). EVs cargo in CAM was significantly enriched of let-7f-5p and depleted of miR-143-3p.
CONCLUSION
Through an unbiased screening of EV-derived sncRNAs, we characterize miRNAs and piRNAs in the EVs cargo as potential biomarkers and modifiers of diverse IIM phenotypes.
PubMed: 38788539
DOI: 10.1016/j.jaut.2024.103255 -
Skin Therapy Letter May 2024Intravenous immune globulin (IVIG) is a manufactured blood product commonly used to treat immunodeficiency syndromes, inflammatory disorders, and autoimmune diseases of... (Review)
Review
Intravenous immune globulin (IVIG) is a manufactured blood product commonly used to treat immunodeficiency syndromes, inflammatory disorders, and autoimmune diseases of the skin. The use of IVIG in dermatology has evolved and expanded over time, serving as a useful therapeutic intervention for several inflammatory skin disorders. In addition to demonstrating efficacy in treating several cutaneous pathologies, IVIG also mitigates the need for steroids or other immunosuppressant medications in many dermatologic diseases. This review highlights the evidence for IVIG use across several dermatologic conditions, emphasizing the dosing regimens and safety considerations.
Topics: Humans; Immunoglobulins, Intravenous; Skin Diseases; Immunologic Factors
PubMed: 38781951
DOI: No ID Found -
Journal of Translational Internal... Apr 2024MicroRNAs (miRNAs) represent a new class of biomarkers in the context of connective tissue disorders. The miRNA expression profiles in peripheral blood mononuclear cells...
BACKGROUND AND OBJECTIVES
MicroRNAs (miRNAs) represent a new class of biomarkers in the context of connective tissue disorders. The miRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of patients with polymyositis (PM) and dermatomyositis (DM) have not been fully elucidated. The objective is to investigate miRNAs expression profile in PBMCs of patients with PM/DM.
METHODS
Microarray technology was used to identify differentially expressed miRNAs in PBMCs obtained from 6 untreated PM/DM patients and 3 healthy controls (HCs). TaqMan-based stem-loop real-time PCR detection was used for validation in a cohort of 34 PM/DM patients and 20 HCs.
RESULTS
Microarray analysis revealed 38 differentially expressed miRNAs (24 up-regulated and 14 down-regulated) in PM/DM patients compared to HCs. Four miRNAs (miR-320a, miR-335-3p, miR-34a-5p and miR-454-3p) were chosen for real-time PCR validation. The expression of miR-34a-5p was significantly upregulated in PM/DM group ( < 0.05). In subgroup analysis, miR-34a-5p was significantly upregulated in interstitial lung disease (ILD) group and DM group ( < 0.001). The level of SIRT1, a validated target of miR-34a, was significantly lower in PBMCs of PM/DM patients compared with HCs.
CONCLUSIONS
MiR-34a-5p may potentially participate in the pathogenesis of PM/DM through SIRT1, and may serve as a potential new biomarker for PM/DM-ILD.
PubMed: 38779122
DOI: 10.2478/jtim-2022-0055 -
Proceedings of the National Academy of... May 2024
Topics: Dermatomyositis; Lung Diseases, Interstitial; Animals; Mice; Interferon-Induced Helicase, IFIH1; Autoimmunity; Disease Models, Animal; Humans
PubMed: 38776374
DOI: 10.1073/pnas.2408646121 -
Journal of Inflammation Research 2024This study aimed to assess liver involvement and investigate its correlation with rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-melanoma...
Liver Involvement is Associated with Higher Risk of Rapidly Progressive Interstitial Lung Disease and Mortality in Anti-Melanoma Differentiation-Associated Gene 5 Antibody- Positive Dermatomyositis.
PURPOSE
This study aimed to assess liver involvement and investigate its correlation with rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5 positive) DM patients.
PATIENTS AND METHODS
This retrospective study included 159 patients diagnosed with anti-MDA5 positive DM or anti-synthetase syndrome (ASyS). Clinical features and laboratory findings were compared between patients with anti-MDA5 positive DM and patients with ASyS. In the anti-MDA5 positive DM cohort, clinical features and laboratory findings between patients with liver involvement and without liver involvement were further compared. The effects of liver involvement on the overall survival (OS) and development of RP-ILD were also analyzed using Kaplan-Meier method and Cox regression analysis.
RESULTS
Levels of serum aspartate aminotransferase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γGT) and alkaline phosphatase (ALP) were all significantly higher in patients with anti-MDA5 positive DM than those in patients with ASyS. In our cohort of anti-MDA5 positive DM patents, 31 patients (34.4%) were complicated with liver involvement. Survival analysis revealed that serum ferritin >1030.0 ng/mL (p<0.001), ALT >103.0 U/l (p<0.001), AST >49.0 U/l (p<0.001), γGT >82.0 U/l (p<0.001), ALP >133.0 U/l (p<0.001), lactate dehydrogenase (LDH)>474.0 U/l (p<0.001), plasma albumin (ALB) <35.7 g/l (p<0.001) and direct bilirubin (DBIL) >2.80 μmol/l (p=0.002) predicted poor prognosis. The incidence of RP-ILD increased remarkably in patients with liver involvement compared to patients without liver involvement (58.1% vs 22.0%, p=0.001). Multivariate analysis revealed that elevated serum ALT level was an independent risk factor for mortality (HR 6.0, 95% CI 2.3, 16.2, p<0.001) and RP-ILD (HR 5.9, 95% CI 2.2, 15.9, p<0.001) in anti-MDA5 positive DM patents.
CONCLUSION
Liver involvement is common in patients with anti-MDA5 positive DM. Elevated serum ALT level was an independent risk factor for RP-ILD and mortality in patients with anti-MDA5 positive DM.
PubMed: 38774443
DOI: 10.2147/JIR.S462721 -
Pediatric Rheumatology Online Journal May 2024Juvenile Dermatomyositis (JDM) is the leading cause of non-infectious inflammatory myopathy in children. It is a heterogeneous group of autoimmune diseases characterized...
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.
Topics: Humans; Male; Dermatomyositis; Autoantibodies; Child, Preschool; Ubiquitin-Activating Enzymes; Morocco
PubMed: 38773611
DOI: 10.1186/s12969-023-00921-9 -
Frontiers in Medicine 2024Interstitial pneumonia is the most common and serious secondary lesion of dermatomyositis. In some cases, patients may develop severe acute pneumonia that can quickly...
Interstitial pneumonia is the most common and serious secondary lesion of dermatomyositis. In some cases, patients may develop severe acute pneumonia that can quickly progress to respiratory failure, resulting in high mortality rates. A 57-year-old woman with dermatomyositis and interstitial pulmonary fibrosis experienced severe hypoxemia due to pulmonary infection. Despite receiving various treatments after entering the intensive care unit (ICU), such as anti-infection therapy, lung recruitment, prone position ventilation, sedative and muscle relaxation, the patient's oxygen saturation continued to decline. Electrical impedance tomography (EIT) monitoring revealed that prone position could not improve ventilation homogeneity. However, the patient's ventilation/perfusion (V/Q) matching significantly improved 10 min after initiation of supine position ventilation combined with inhalation of nitric oxide (iNO). The patient's PaO/FiO (P/F) ratio increased from 86 mmHg to 150 mmHg at 30 min post-treatment. iNO treatment continued for 2 days. Then the patient's condition improved and she was successfully weaned off the ventilator with rigorous monitoring and symptomatic care. The implementation of mechanical ventilation combined with iNO therapy rapidly improved V/Q matching and oxygenation in a patient with hypoxemia caused by dermatomyositis complicated with interstitial pneumonia. This approach successfully avoided the need for invasive extracorporeal membrane oxygenation (ECMO) support.
PubMed: 38765258
DOI: 10.3389/fmed.2024.1371183