Search Results (6)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a broad and varied clinical presentation. In the absence of definite diagnostic criteria, establishing an SLE diagnosis remains challenging. This case series illustrates that other diseases, such as primary immunodeficiencies and monogenic interferonopathies, can closely mimic SLE, even in the presence of its typical serological markers. Recognizing these disease mimickers is crucial to avoid premature conclusions in clinical evaluation and to ensure the initiation of appropriate therapy. Especially in cases of atypical presentation, unusual disease progression, or resistance to standard therapy, alternative diagnoses should be considered. In this overview, we discuss the diagnostic approach for patients with SLE-like manifestations and provide a comprehensive review of diseases that may mimic SLE. Full article

Introduction: Aicardi-Gouteres syndrome (AGS) is a monogenic interferonopathy characterized by early onset, dysregulation of skin (chilblain lesions), brain, and immune systems (fever, hepatomegaly, glaucoma, arthritis, myositis, and autoimmune activity). The disease looks like TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infection with early-onset encephalopathy resulting in severe neuropsychological disability. Case description: A six-year-old girl has been suffering from generalized seizures, fever episodes, severe psychomotor development delay, and spastic tetraparesis since the first year of her life. Her two elder brothers died at a young age from suspected infantile cerebral palsy (ICP). Other siblings (younger brother and two elder sisters) are as healthy as their parents. The girl was diagnosed with juvenile dermatomyositis at 5.5 years. Basal ganglia, periventricular, and cerebellum calcifications; hypoplasia of the corpus callosum; and leukodystrophy were detected on CT. The IFN-I score was 12 times higher than normal. The previously not described nucleotide variant c.434G > C (chr 20:36935104C > G; NM_015474) was detected in exon 4 of the SAMHD1 gene in the homozygous state, leading to amino acid substitution p.R145P. Aicardi-Goutières syndrome 5 was diagnosed. Her treatment included corticosteroids, methotrexate, and tofacitinib 5 mg twice a day and it contributed to health improvements. The following brain CT depicted the previously discovered changes without the sign of calcification spreading. Conclusions: Early diagnosis of AGS is highly important as it allows starting treatment in a timely manner. Timely treatment, in return, can help avoid the development/progression of end-organ damage, including severe neurological complications and early death. It is necessary to spread information about AGS among neurologists, neonatologists, infectious disease specialists, and pediatricians. A multidisciplinary team approach is required. Full article

STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans. Full article

Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies. Full article

Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes. Full article

Interferon-stimulated genes (ISGs) are a set of genes whose transcription is induced by interferon (IFN). The measure of the expression of ISGs enables calculating an IFN score, which gives an indirect estimate of the exposition of cells to IFN-mediated inflammation. The measure of the IFN score is proposed for the screening of monogenic interferonopathies, like the Aicardi-Goutières syndrome, or to stratify subjects with systemic lupus erythematosus to receive IFN-targeted treatments. Apart from these scenarios, there is no agreement on the diagnostic value of the score in distinguishing IFN-related disorders from diseases dominated by other types of cytokines. Since the IFN score is currently measured in several research hospitals, merging experiences could help define the potential of scoring IFN inflammation in clinical practice. However, the IFN score calculated at different laboratories may be hardly comparable due to the distinct sets of IFN-stimulated genes assessed and to different controls used for data normalization. We developed a reliable approach to minimize the inter-laboratory variability, thereby providing shared strategies for the IFN signature analysis and allowing different centers to compare data and merge their experiences. Full article