High-throughput transcriptomic profiling of mRNAs and lncRNAs in the dermatomyositis muscle by RNA sequencing

Background:Dermatomyositis(DM)is an idiopathic inflammatory myopathy(IIM).In this study,we investigated the mRNAs and long noncoding RNAs(lncRNAs)in muscle biopsy specimens that are differentially expressed among patients with DM,patients with other IIM,and healthy controls(HCs).Methods:In total,three patients with DM,10 patients with other IIM,and three HCs were included.Muscle biopsy specimens were collected for RNA-sequencing.Gene ontology and pathway analyses were employed to characterize the biological processes and signaling pathways.Results:Compared with HCs,372 differentially expressed mRNAs were identified within the DM group,including 275 upregulated and 97 downregulated ones.Moreover,692 differentially expressed lncRNAs were identified in the DM group compared with HCs,of which 407 were upregulated and 285 were downregulated.Bioinformatic analysis indicated that the type-Ⅰ interferon signaling pathway and biological processes of innate immunity were significantly influenced by the differentially expressed mRNAs.Notably,11 of the top 20 upregulated mRNAs were involved in the type-Ⅰ interferon signaling pathway.Reverse transcription polymerase chain reaction analysis verified the RNA-sequencing data.Target gene prediction analysis suggested that the lncRNA NONHSAG043573.2 potentially targeting transporter associated with antigen processing 1,a key regulator of interferon signaling genes,might play an important role in the pathogenesis of DM.Conclusions:Our study assessed the transcriptomic profiles of differentially expressed mRNAs and lncRNAs in the DM muscle tissue and revealed that the upregulated mRNAs are significantly involved in the innate immune response and the type-Ⅰ interferon signaling pathway,which might play important roles in the pathogenesis of DM.

Coexistent ankylosing spondylitis and intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

To the Editor,Ankylosing spondylitis(AS)is a chronic inflammatory rheumatic disease mainly affecting the axial skeleton,with chronic back pain and spinal stiffness as primary presenting symptoms.1 AS is heritable and exhibits familial aggregation.2 The disease course is frequently complicated with other immune diseases,cardiovascular disease,and depression3.

Multisystem inflammatory syndrome in adults associated with COVID-19:A rare life-threatening complication

To the Editor,Herein,we report a case of a 49-year-old Caucasian man with a medical history of gastroesophageal reflux disease,occasional premature ventricular contractions,and unvaccinated against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)who presented with myalgias,fevers,and right-sided neck swelling approximately 26 days after he had tested positive for SARS-CoV-2 and 21 days after receiving the casirivimab–imdevimab(REGEN-COV)infusion.His initial workup showed leukocytosis and thrombocytopenia(platelets:108×109/L,reference range[RR]:150−328×109/L).The SARS-CoV-2 rapid antigen-detection test was negative.The patient was started on intravenous antibiotics for presumed lymphadenitis;however,his fevers persisted,with subsequent development of worsening thrombocytopenia at 91×109/L and increasing C-reactive protein(CRP)and erythrocyte sedimentation rate(ESR),with peak values at 13.4mg/dL(RR:<0.8 mg/dL)and 35 mm/1 h(RR:0−10 mm/1 h),respectively.

Severe IgA vasculitis with features of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in a 60‐year‐old male treated with plasmapheresis

Objective:To explore a possible association between systemic immunoglobulin A(IgA)vasculitis and RS3PE syndrome and to investigate specific treatment regimens for adults who present with IgA vasculitis with renal involvement.Methods:The patient was treated with plasmapheresis and fresh frozen plasma(FFP)every other day with 1g methylprednisolone daily for three days followed by oral prednisone taper.Mycophenolate mofetil twice daily and trimethoprim‐sulfamethoxazole for Pneumocystis jirovecii prophylaxis was started.In total the patient received two cycles of plasmapheresis and fresh frozen plasma.Results:The patient's renal function drastically improved with resolution of both abdominal pain and nausea.Conclusion:We illustrate a possible association between systemic IgA vasculitis and RS3PE syndrome,and this case demonstrates IgA vasculitis with renal involvement that acutely resolved with high‐dose glucocorticoids and plasmapheresis.Additionally,our specific treatment regimen can be a potential standard of care for adults who present with IgA vasculitis with renal involvement.

Histological evolution of IgG4 related disease

To the Editor,IgG4‐related disease(IgG4‐RD)is a multisystem auto‐immune disorder with propensity to involve the kidneys.The clinical presentation,1 diagnostic classification criteria 2 and grading of disease activity(Responder Index)3 of IgG4‐RD have been well established,however there is scarce data on histological evolution of this disease entity ensuing immunosuppressive treatment.There is a concern that the dense fibrotic lesions of IgG4‐RD could remain obstinate,notwithstanding immunosuppressive therapy,4 thereby leaving the affected organ with permanent scarring.We present the case of a 57‐year‐old man with multi‐system IgG4‐RD in whom the dense lympho‐plasmocytic intersti-tial inflammation and the typical whorl‐like storiform fibrosis observed in initial kidney biopsy showed a near complete resolution following 4 months of immuno-suppressive therapy.

Role of β2-glycoprotein I in the pathogenesis of the antiphospholipid syndrome

Antiphospholipid syndrome(APS)is typically characterized by increased levels of three classes of antiphospholipid antibodies,namely lupus anticoagulant,anti-β2-glycoprotein I(anti-β2GPI),and anticardiolipin antibodies.β2-Glycoprotein(β2GPI)is a phospholipid-binding protein composed of five domains(DI-V)and a major antigen in APS.β2GPI is expressed on the surfaces of several cell types,including endothelial cells,monocytes,trophoblast cells,and platelets.Its binding to the anti-β2GPI antibody triggers downstream signaling events and ultimately exerts a variety of cellular effects.β2GPI modulates hemostasis and the complement system,as well as playing an important role in APS-associated vascular injury.Therefore,studying β2GPI will help elucidate the pathogenesis of APS and improve the treatment of patients with this condition.This review will mainly focus on the structure and function of β2GPI,as well as its implication in the pathogenesis of APS.

Identification and functional analysis of shared gene signatures between systemic lupus erythematosus and Sjogren's syndrome

Background:Systemic lupus erythematosus(SLE)is an autoimmune disease that can affect multiple systems.Sjogren's syndrome(SS)is an autoimmune disease that may be primary SS(pSS)or occur together with other autoimmune diseases,including SLE.This study aimed to explore the shared gene signatures in SLE and pSS.Methods:Gene expression data sets of SLE(GSE50772 and GSE81622)and pSS(GSE84844 and GSE48378)were obtained and analyzed for differentially expressed genes(DEGs)in peripheral blood mononuclear cells(PBMCs).A protein–protein interaction(PPI)network was constructed.Gene ontology(GO)and KEGG pathway enrichment analysis were carried out for the DEGs.Results:We screened 232 and 110 DEGs from the SLE and pSS data sets,respectively.We found 32 shared DEGs,which were all upregulated in patients compared with controls.Among these 32 DEGs,11 genes showed a more than twofold change in all data sets(IFI27,IFI44L,RSAD2,IFIT1,IFI44,USP18,IFI6,HERC5,EPSTI1,OAS1,and OAS3).PPI analysis showed that 29 genes interacted with each other.GO analysis showed that these 32 shared DEGs were mainly enriched in biological processes associated with the type Ⅰ interferon signaling pathway,defense response to viruses,response to viruses,negative regulation of viral genome replication,and the immune response.Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that these 32 DEGs were related to virus infection.Conclusion:This study showed that alterations to biological processes associated with the response to virus infection play critical roles in both SLE and pSS.

Association of immunoglobulin G4-related disease with a family history of malignancy:A retrospective study of 168 cases

Objective:Immunoglobulin G4-related disease(IgG4-RD)is a systemic immune-mediated fibroinflammatory condition.Previous studies have indicated relationships between malignancy and autoimmunity.This retrospective cohort study aimed to determine IgG4-RD incidence and clinical features in patients with a family history of malignancy.Methods:To analyze the relationship between IgG4-RD and family history of malignancy,we reviewed IgG4-RD patients with a family history of malignancy diagnosed in various departments in West China Hospital,Sichuan University from December 2012 to September 2019.Clinical data and laboratory features were compared between IgG4-RD patients with and without a family history of malignancy.Results:Among 168 enrolled patients with IgG4-RD,22(13.1%)had a family history of malignancy.The most frequently involved system in family members with malignancy was the digestive system(38.5%).Among patients with a family history of malignancy,the most frequently involved organs in IgG4-RD were the pancreas(31.9%)and lymph nodes(31.9%).Age at symptom onset was older in IgG4-RD patients with a family history of malignancy than in patients without a family history of malignancy(50–59 years:36.3%vs.16.4%,p=0.0393).Hemoglobin(p=0.0172)and albumin(p=0.0247)levels were higher and globulin(p=0.0232)levels were lower in patients with a family history of malignancy.Conclusions:Our findings suggest that a family history of malignancy may be associated with IgG4-RD development.We hypothesize that genetic susceptibility may be involved in the pathogenesis of IgG4-RD.

Genetic evidence suggesting the predicted causality between osteoarthritis and cardiovascular diseases

Background:Epidemiological studies have shown a close association between osteoarthritis(OA)and cardiovascular disease(CVD),but reliable evidence needs to be provided.We performed a two-sample Mendelian randomization(MR)study to examine the potential causal effect between OA and CVD.Methods:Exposures were self-reported OA,knee osteoarthritis(KOA),and hip osteoarthritis(HOA).The outcomes were 12 CVDs,including heart failure,atrial fibrillation,coronary artery disease,pulmonary embolism,stroke and its subtypes,myocardial infarction,coronary heart disease,and primary hypertension.All outcomes were obtained from published genomewide association studies.The inverse-variance weighted method was used as the primary MR analysis.Heterogeneity tests and sensitivity analyses were conducted to validate the accuracy of the MR results.Results:Self-reported OA increased the incidence of small vessel stroke(odds ratio[OR]=1.25,95%confidence interval[CI]:1.02–1.52,p=0.03)and primary hypertension(1.01[1.00–1.02],p<0.01).HOA increased the incidence of stroke(1.06[1.01–1.11],p=0.02)and two subtypes(cardioembolic stroke:1.12[1.02–1.23],p=0.02;ischemic stroke:1.06[1.01–1.11],p=0.03).Patients with KOA had an increased risk of heart failure(1.10[1.04–1.16],p<0.01),atrial fibrillation(1.08[1.02–1.13],p<0.01),small vessel stroke(1.21[1.06–1.39],p=0.01),and primary hypertension(1.01[1.01–1.02],p<0.01).Conclusions:Patients with OA have an increased risk of several CVDs.The causality of this relationship may have clinical implications for improving the quality of prevention and treatment.

Old and new damage‐associated molecular patterns (DAMPs) in autoimmune diseases

All organisms living in complex environments have evolved effective mechanisms of dynamic responses to extracellular stimuli.The immune system activates when damaged or injured cells release damage‐associated molecular patterns(DAMPs).In addition to well‐characterized DAMPs such as high‐mobility group box 1 and adenosine triphosphate,studies on new classes of DAMPs have emerged.Here,we review recent reports of a new class of isoprenoid‐derived DAMPs,including farnesyl pyrophosphate and geranylgeranyl pyrophosphate,both of which are pivotal metabolic inter-mediates of the mevalonate pathway.We also explore the roles of old and new DAMPs in autoimmune diseases that result from dysregulated inflammation.The findings highlight that understanding the functional mechanisms of DAMPs is important to enrich the DAMP family and decipher their immunoregulatory mechanisms to provide new therapeutics for the prevention and treatment of autoimmune diseases.

Inflammatory bowel disease‐related periostosis

Key point Periosteal reaction and bone absorption could be manifested in ulcerative colitis.A 61‐year‐old woman presented with a 6‐year history of polyarthritis and a 12‐year history of recurrent bloody stool.Twelve years before presentation,she had been diagnosed with ulcerative colitis characterized by recurrent bloody stool and anemia.As maintenance treatment,she regularly took mesalazine at 1 g three times daily and prednisone at 10 mg once daily;however,the disease remained active.Six years before presentation,the patient developed polyarthritis and deformity in her wrists,metacarpophalangeal joints,proximal interphalangeal joints,and knees.Physical examination revealed short deformity of the left middle finger,restricted movement of the wrists,and swelling of the right knee with tenderness.

Noncanonical autophagy in systemic lupus erythematosus

Background:Noncanonical autophagy is generally described as a lysosomal degradation process that requires only a subset of the core autophagy-related proteins to form functional autophagosomes.Review:Accumulating evidence implicates noncanonical autophagy pathways in expanding the versatility of the immune system via regulation of functions that include antigen presentation,dead cell clearance,inflammatory cytokine production,and immune cell homeostasis.In this review,we use microtubuleassociated protein 1 light chain 3-associated phagocytosis(LAP)as an example of noncanonical autophagy,describing its distinctive molecular machinery and highlighting recent advances in its functioning in immunity.We also discuss the direct and indirect evidence supporting the pathogenic significance of abnormal levels of LAP in systemic lupus erythematosus(SLE).Future Perspectives:A better understanding of the role of noncanonical autophagy in SLE may reveal crucial information about the disease pathology,providing direction for therapeutic developments and improved prognosis.

Investigation of COVID-19 infection in patients with polymyalgia rheumatica during the predominance of the omicron variant

Background::Polymyalgia rheumatica (PMR) is an inflammatory disease that affects the older adult population. The aim of this study was to investigate the risk and prognosis associated with the coronavirus disease 2019 (COVID-19) infection among patients diagnosed with PMR during the predominance of the Omicron variant.Methods::In this retrospective study, we included a cohort of patients with PMR who met the 2012 European League Against Rheumatism/American College of Rheumatology classification criteria or the 1982 PMR diagnostic criteria and tracked their progress over time. The diagnosis of COVID-19 was based on the clinical manifestations and laboratory tests. We collected demographic information, PMR disease activity, treatment data, and clinical data related to COVID-19.Results::In total, 101 patients diagnosed with PMR were enrolled. Most patients with PMR exhibited low disease activity. Of the total cohort, 81 patients (80.2%) were categorized as individuals diagnosed with COVID-19, while the remaining 20 (19.8%) were not diagnosed with COVID-19. Among the patients with PMR diagnosed with COVID-19, 65 (80.2%) exhibited the presence of the COVID-19 antigen, while 16 (19.8%) tested positive for COVID-19 RNA. Most COVID-19 patients with PMR were classified as having mild disease (72, 88.9%). Two cases were identified within the confirmed infected group, resulting in a recurrence rate of 2.5% (2/81). Conversely, no relapses were observed in the non-infected group (0/20). In our multivariate logistic regression analysis, we found that pre-COVID-19 PMR disease activity was an independent risk factor for COVID-19 infection (odds ratio = 30.00, 95% confidence interval: 2.137-421.117, p = 0.012). Conclusion::The increased susceptibility to COVID-19 may be influenced by the pre-existing disease activity of PMR.

Th17/Treg balance and factors related to autoimmune hepatitis

Background:Although Th17 cells and regulatory T cells play critical roles in autoimmune hepatitis,the balance between them in acute and chronic immune hepatitis is not well‐studied.The objective of this study was to explore the role of Th17/Treg balance in autoimmune hepatitis.Methods:Thirty female Wistar rats were randomly divided into the following three groups:acute model(AC),chronic model(CC),and healthy control(HC).Aspartate aminotransferase,alanine aminotransferase,and bilirubin levels were measured.Peripheral blood interleukin(IL)‐17,IL‐6,IL‐10,and transforming growth factor‐βcytokine levels were also assessed.Flow cytometry was used to detect changes in the Th17 cell and Treg cell frequency,and the Th17/Treg ratio was calculated.Results:The frequency of Th17 cells and Treg cells were both increased(p<0.05)and the Th17/Treg ratio was higher in the AC group compared with those in the HC group(p<0.05).Th17 cell levels were significantly lower and Treg cell levels were significantly higher in the CC group,compared with those in the AC group(p<0.05).In addition,the Th17/Treg ratio was lower in the CC group compared with that in the HC group(p<0.05).Conclusion:The Th17/Treg ratio was increased in the acute immune liver injury model and decreased in the chronic liver injury model.Th17/Treg imbalance may play a critical role in liver injury occurrence and development.

Fibroblast diversity and clinical associations in systemic sclerosis

Fibroblasts serve as the primary source of extracellular matrix and play a crucial role in the remodeling of fibrotic tissue.Beyond their structural functions,fibroblasts also influence inflammatory processes and angiogenesis through the release of various mediators,potentially contributing to the inflammatory and vasculopathic aspects of systemic sclerosis(SSc).A recent study published in J Invest Dermatol delves into the varied functionalities of fibroblast populations and their clinical implications.

Tocilizumab in rheumatoid arthritis-associated peripheral ulcerative keratitis:A case report

We report a case of rheumatoid arthritis-associated peripheral ulcerative keratitis(PUK)successfully treated with tocilizumab.Despite having been treated with systemic corticosteroids and several disease-modifying antirheumatic drugs and having,received corneal transplantation,the patient lost sight in the left eye.Tocilizumab resulted in a good response,with her systemic illness controlled and the progression of corneal lesions prevented.Tocilizumab may be an additional tool for patients with rheumatoid arthritis associated PUK that is refractory to other drugs.

Artificial intelligence in rheumatoid arthritis research:A bibliometric analysis from 2004 to 2023

Background::Artificial intelligence(AI)holds promise for the screening,diagnosis,and management of patients with rheumatoid arthritis(RA).This study explores the current status of AI in RA from 2004 to 2023 using bibliometric analysis and outlines prospective research trends and directions.Methods::The Web of Science Core Collection database was searched for studies related to AI in patients with RA between 2004 and 2023.VOSviewer was used for bibliometric analysis.Results::A total of 601 articles from 65 countries,primarily the United States of America,China,and the United Kingdom,were included.The research revealed that the number of global studies on AI in RA surged in 2019,with the United States of America and China producing the highest numbers of articles.Brigham and Women's Hospital emerged as the leading research institution,whereas Frontiers in Immunology was the journal with the most articles on this topic.Keywords such as"rheumatoid arthritis,""machine learning,""artificial intelligence,"and"inflammation"were frequently used to indicate their significance in the field.Conclusions::The synergy of AI and big data can enhance screening,early diagnosis,therapeutic decision-making,and ground-up drug discovery for patients with RA.AI technology can assist rheumatologists more effectively in diagnosing and predicting personalized and efficacious therapeutic drugs early in disease progression and providing continuous monitoring.

Single nucleotide polymorphism(SNP)in genes of lupus:A Philippine study(SIGLA-PH)

Background:Systemic lupus erythematosus(SLE)is a complex prototypic autoimmune disease,with a prevalence of 20–150 per 100,000,most commonly affecting women at child-bearing age.Genome-wide association studies and fine mapping of candidate regions have paved the way for greater understanding of SLE as a disease of genetic–environmental susceptibility and the functions of the genes involved.Method:This study was conducted to determine the association of selected single nucleotide polymorphisms(SNPs)from established genomic databases based on theoretical risk and protective odds ratios>2.5 or<0.40)to susceptibility of developing SLE among Filipinos.Results:We analyzed data from 310 SLE patients and 318 controls.We identified eight significant SNPs namely rs9271100,rs9271366,rs9272105,rs9275328,rs2647087,rs12734338,rs17885098,and rs3883013 to be associated with an increased risk of developing SLE among Filipinos.Conclusion:Eight SNPs were found to be associated with the development of SLE among Filipinos.Similar to previous genetic studies in lupus patients,majority of the SNPs were found in the major histocompatibilty complex genes in the HLA region.Our study identified two unique SNPs that will be validated as potential diagnostic markers for SLE.The findings of this study may contribute to the development of a polygenic risk score in determining susceptibility to SLE among Filipinos.

Long-term prognosis of focal segmental glomerulosclerosis treated with therapeutic low-density lipoprotein-apheresis in patients with severe kidney dysfunction and proteinuria

Background:The prognosis of focal segmental glomerulosclerosis patients with nephrotic syndrome is estimated to be 10%-20%in 5 years and 30%-50%in 10 years,leading to end-stage kidney disease.The response rate with steroid therapy is 40%-60%.Therapeutic low-density lipoprotein-apheresis(LDL-A)may be effective in patients with steroid resistance.Information regarding the long-term prognosis of patients with focal segmental glomerulosclerosis receiving this therapy is scarce.Methods:We investigated the effectiveness of treatment in 50 patients with primary focal segmental glomerulosclerosis diagnosed between 1961 and 2017 at Kanazawa University Hospital and related facilities.The patients were observed at least 12 months after biopsy or until end-stage kidney disease occurrence or death.Results:LDL-A was performed in four patients who presented with steroidresistant nephrotic syndrome(two patients had concurrent acute renal failure for which hemodialysis was performed).In comparison with 17 patients who did not receive LDL-A after 1989,the LDL-A group had higher urinary protein excretion(13.7 vs.5.2 g/day,P=0.053)and serum creatinine(4.11 vs.1.65 mg/dL)levels at onset,and a numerically higher remission rate(75.0%vs.58.7%)compared with the nonlipoprotein-apheresis group.Conclusion:Therapeutic LDL-A can be performed for critical cases and may improve the remission rate.

Azathioprine-induced pancytopenia:A case report

Azathioprine(AZA)is commonly used as immunosuppressive therapy for autoimmune diseases,including systemic lupus erythematosus(SLE).Myelosuppression is a common side effect of AZA.Here we report a case of severe myelosuppression following AZA therapy in a 15-year-old girl despite a normal thiopurine methyltransferase(TPMT)level.She had been receiving AZA for SLE and presented with neutropenic fever and pancytopenia.AZA was stopped.After stopping AZA,her blood counts steadily improved.When TPMT genotyping results were normal,AZA was reintroduced.Pancytopenia reappeared after starting AZA,despite normal TPMT genotype.AZA was replaced with mycophenolate mofetil which consequently resulted in improvement of blood counts.It is essential to understand the temporal relationship between AZA use and pancytopenia onset in patients with normal TPMT activity.This case illustrates that regular monitoring of blood cell counts should be routine practice after starting AZA regardless of TPMT activity.