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ID PMID Title PublicationDate abstract
33832541 Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface an 2021 Apr 8 BACKGROUND: Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg-/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg-/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs- serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one-to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. RESULTS: Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ~ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89-0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48-15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22-88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88-0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39-871.5). CONCLUSIONS: Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg-/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation.
34827064 Autoantibodies and Rheumatologic Manifestations in Hepatitis C Virus Infection. 2021 Oct 20 HCV is a virus that can cause chronic infection which can result in a systemic disease that may include many rheumatologic manifestations such as arthritis, myalgia, sicca syndrome, cryoglobulinemia vasculitis as well as other non-rheumatological disorders (renal failure, onco-haematological malignancies). In this population, the high frequency of rheumatoid factor (45-70%), antinuclear (10-40%) and anticardiolipin (15-20%) antibodies is a B-cell mediated finding sustained by the infection. However, the possibility that a primitive rheumatic pathology may coexist with the HCV infection is not to be excluded thus complicating a differential diagnosis between primitive and HCV-related disorders.
33447495 The Delay of Diagnosis in Spondyloarthropathy Patients in a Tertiary Hospital in Saudi Ara 2021 Jan 11 Objective Seronegative spondyloarthropathies (SpA) are a group of rheumatological disorders that share the common feature of being rheumatoid factor negative. Inflammation of the sacroiliac joint is considered the hallmark of ankylosing spondylitis (AS). On the other hand, psoriatic arthritis (PsA) affects patients with psoriasis. It is characterized by asymmetrical oligoarticular arthritis. Involvement of the distal interphalangeal joint is a unique feature of PsA. Enteropathic arthritis (EnA) involves the presence of inflammatory arthropathy in patients with inflammatory bowel disease (IBD). These diseases are strongly associated with the HLA-B27 gene. Although they are significantly disabling, their diagnosis has been frequently delayed. Early diagnosis is associated with early treatment, and thus better disease outcomes. The aim of this study was to evaluate the diagnostic delay (DD), that is, the duration between onset of symptoms and diagnosis, of SpA patients and its relation to the demographic characteristics, disease activity, measured by ankylosing spondylitis disease activity score (ASDAS) and bath ankylosing spondylitis disease activity index (BASDAI) scores, and the HLA-B27 status of Saudi SpA patients. Methods The data of 94 patients who were diagnosed with SpA were collected from medical records and from them personally. The data included patient demographics, age at diagnosis, delay of diagnosis, in years, disease activity (BASDAI and ASDAS scores), HLA-B27 status and C-reactive protein levels (CRP). The data were analyzed using Statistical Package for the Social Sciences for Windows version 21.0 (SPSS Inc., Chicago, IL, USA). Results 50% of patients were females. The mean DD was (mean ± SD) 4.98 ± 6.00 (range: 0-35). The average age of symptoms onset was 30.70 ± 11.30 (range: 8-59) and the average age at diagnosis was 35.65 ± 10.80 (range: 16-60). The mean BASDAI and ASDAS scores were 3.05 ± 2.21 and 2.29 ± 1.01, respectively. The majority of the patients had high disease activity (35.1 %). 25.0% were HLA-B27 positive. 83.7 % had normal CRP. There was no statistically significant difference between DD and gender, HLA-B27 status, ASDAS and BASDAI scores, and CRP. The DD was significantly higher in AS patients when compared to PsA (p-value= 0.048) and EnA patients (p-value < 0.0001). There was a statistically significant weak anticorrelation between DD and the age at symptoms onset in PsA patients (r-value= -0.39, p-value= 0.003). Age at diagnosis was statistically significantly higher in patients with PsA when compared to EnA. There was no correlation between DD and the disease activity in SpA patients. Conclusion The means of DD in AS, PsA, and EnA patients were 6.69 ± 5.83, 3.67 ± 6.42 and 2.00 ± 1.60, respectively. DD was greater in AS patients when compared to PsA and EnA patients. Early detection and referral to rheumatologists should be addressed, as early intervention is associated with favorable disease outcomes.
32772240 Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Produ 2021 Feb Sjögren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.
33669065 Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulat 2021 Feb 25 Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4(+) T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sjögren's syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis.
34099632 Targeting angiogenesis for fracture nonunion treatment in inflammatory disease. 2021 Jun 7 Atrophic fracture nonunion poses a significant clinical problem with limited therapeutic interventions. In this study, we developed a unique nonunion model with high clinical relevance using serum transfer-induced rheumatoid arthritis (RA). Arthritic mice displayed fracture nonunion with the absence of fracture callus, diminished angiogenesis and fibrotic scar tissue formation leading to the failure of biomechanical properties, representing the major manifestations of atrophic nonunion in the clinic. Mechanistically, we demonstrated that the angiogenesis defect observed in RA mice was due to the downregulation of SPP1 and CXCL12 in chondrocytes, as evidenced by the restoration of angiogenesis upon SPP1 and CXCL12 treatment in vitro. In this regard, we developed a biodegradable scaffold loaded with SPP1 and CXCL12, which displayed a beneficial effect on angiogenesis and fracture repair in mice despite the presence of inflammation. Hence, these findings strongly suggest that the sustained release of SPP1 and CXCL12 represents an effective therapeutic approach to treat impaired angiogenesis and fracture nonunion under inflammatory conditions.
34036345 Sjögren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to e 2021 Jul 23 Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.
32620868 CP-25 alleviates antigen-induced experimental Sjögren's syndrome in mice by inhibiting JA 2021 Aug The etiology of primary Sjögren's syndrome (pSS) remains unknown, and there is no complete curative drug. In this study, we treated a mouse model of the submandibular gland (SG) protein-immunized experimental Sjögren's syndrome (ESS) with paeoniflorin-6'-O-benzene sulfonate (termed CP-25) to evaluate the potential therapeutic effects of CP-25. Through in vivo experiments, we found that CP-25 increased saliva flow, alleviated the salivary gland indexes, and improved tissue integrity in the ESS model. The viability of splenocytes and B-lymphocyte migration from spleen were reduced in ESS mice. Furthermore, CP-25 decreased the expression of IgG antibodies, anti-SSA and anti-SSB antibodies and modulated the levels of cytokines in the serum of SS mice. The numbers of total B lymphocytes, plasma cells (PCs), and memory B cells diminished in the salivary gland. Increased expression of the JAK1-STAT1-CXCL13 axis and IFNα was found in human tissue isolated from pSS patients. In vitro, after stimulation with IFNα, the levels of CXCL13 mRNA and CXCL13 in human salivary gland epithelial cells (HSGEC) increased, while CP-25 counteracted the secretion of CXCL13 and downregulated the expression of CXCL13. IFN-α activated the JAK1-STAT1/2-CXCL13 signaling pathway in HSGEC, which was negatively regulated by additional CP-25. As a consequence, B-cell migration was downregulated in coculture with IFN-α-stimulated HSGEC. Taken together, this study demonstrated that the therapeutic effects of CP-25 were associated with the inhibition of the JAK1-STAT1/2-CXCL13 signaling pathway in HSGEC, which impedes the migration of B cells into the salivary gland. We identified the underlying mechanisms of the therapeutic effect of CP-25 and provided an experimental foundation for CP-25 as a potential drug in the treatment of the human autoimmune disorder pSS.
34284720 Differential long non-coding RNA expression profile and function analysis in primary Sjogr 2021 Jul 20 BACKGROUND: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by abnormal immune cell activation. This study aimed to investigate differentially expressed long non-coding RNA (lncRNA) in peripheral blood mononuclear cells (PBMCs) in patients with pSS to identify lncRNAs that affect pSS pathogenesis. METHODS: Total RNA was extrated from PBMCs of 30 patients with pSS and 15 healthy persons. Transcriptome sequencing was used to screen differentially expressed lncRNAs and mRNAs in 8 RNA samples from the discovery cohort. The differentially expressed mRNAs underwent functional enrichment analysis. A protein interaction relationship (PPI) and competitive endogenous RNA (ceRNA) network was constructed. Real-time PCR was used to validate screened lncRNAs in all 45 RNA samples.. RESULTS: 1180 lncRNAs and 640 mRNAs were differentially expressed in pSS patients (fold change > 2 in healthy persons). The PPI network was constructed with 640 mRNAs and a ceRNA network with four key lncRNAs (GABPB1-AS1, PSMA3-AS1, LINC00847 and SNHG1). Real-time PCR revealed that GABPB1-AS1 and PSMA3-AS1 were significantly up-regulated 3.0- and 1.4-fold in the pSS group, respectively. The GABPB1-AS1 expression level was positively correlated with the percentage of B cells and IgG levels. CONCLUSIONS: GABPB1-AS1 was significently up-regulated in pSS patients, and its expression level is positively correlated with the percentage of B cells and IgG levels. GABPB1-AS1 may be involved in the pathogenesis of pSS and may be a promising biological marker.
34546444 Functional roles of polyamines and their metabolite acrolein in eukaryotic cells. 2021 Oct Among low molecular weight substances, polyamines (spermidine, spermine and their precursor putrescine) are present in eukaryotic cells at the mM level together with ATP and glutathione. It is expected therefore that polyamines play important roles in cell proliferation and viability. Polyamines mainly exist as a polyamine-RNA complex and regulate protein synthesis. It was found that polyamines enhance translation from inefficient mRNAs. The detailed mechanisms of polyamine stimulation of specific kinds of protein syntheses and the physiological functions of these proteins are described in this review. Spermine is metabolized into acrolein (CH(2) = CH-CHO) and hydrogen peroxide (H(2)O(2)) by spermine oxidase. Although it is thought that cell damage is mainly caused by reactive oxygen species (O(2)(-), H(2)O(2), and •OH), it was found that acrolein is much more toxic than H(2)O(2). Accordingly, the level of acrolein produced becomes a useful biomarker for several tissue-damage diseases like brain stroke. Thus, the mechanisms of cell toxicity caused by acrolein are described in this review.
33562815 Rab27a Contributes to Cathepsin S Secretion in Lacrimal Gland Acinar Cells. 2021 Feb 5 Altered lacrimal gland (LG) secretion is a feature of autoimmune dacryoadenitis in Sjögren's syndrome (SS). Cathepsin S (CTSS) is increased in tears of SS patients, which may contribute to disease. Rab3D and Rab27a/b isoforms are effectors of exocytosis in LG, but Rab27a is poorly studied. To investigate whether Rab27a mediates CTSS secretion, we utilized quantitative confocal fluorescence microscopy of LG from SS-model male NOD and control male BALB/c mice, showing that Rab27a-enriched vesicles containing CTSS were increased in NOD mouse LG. Live-cell imaging of cultured lacrimal gland acinar cells (LGAC) transduced with adenovirus encoding wild-type (WT) mCFP-Rab27a revealed carbachol-stimulated fusion and depletion of mCFP-Rab27a-enriched vesicles. LGAC transduced with dominant-negative (DN) mCFP-Rab27a exhibited significantly reduced carbachol-stimulated CTSS secretion by 0.5-fold and β-hexosaminidase by 0.3-fold, relative to stimulated LGAC transduced with WT mCFP-Rab27a. Colocalization of Rab27a and endolysosomal markers (Rab7, Lamp2) with the apical membrane was increased in both stimulated BALB/c and NOD mouse LG, but the extent of colocalization was much greater in NOD mouse LG. Following stimulation, Rab27a colocalization with endolysosomal membranes was decreased. In conclusion, Rab27a participates in CTSS secretion in LGAC though the major regulated pathway, and through a novel endolysosomal pathway that is increased in SS.
33455918 Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that conf 2021 Jan 17 OBJECTIVES: To determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function. METHODS: Conditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants. RESULTS: Conditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced. CONCLUSIONS: SLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.
34477112 Short- and long-term prognosis of acute critically ill patients with systemic rheumatic di 2021 Sep 3 Patients with systemic rheumatic disease (SRD) share the risks of multi-organ flare-up, cardiovascular diseases, and immunosuppression. Such situations can lead to an acute critical illness. The present study describes the clinical features of SRD patients admitted to the intensive care unit (ICU) and their short- and long- term mortality.We performed a multicentre retrospective study in 10 French ICU in Lyon, France. Inclusion criteria were SRD diagnosis and admission for an acute organ failure. The primary endpoint was ICU mortality.A total of 271 patients were included. SRD included systemic lupus erythematosus (23.2% of included patients), vasculitis (10.7%), systemic sclerosis (10.7%), idiopathic inflammatory myopathy (6.3%), and other connective tissue disorders (rheumatoid arthritis, Sjögren and Sharp syndromes; 50.9%). Initial organ failure(s) were shock (43.5% of included patients), acute kidney injury (30.5%), and acute respiratory failure (23.2%). The cause(s) of ICU admission included sepsis (61.6%), cardiovascular events (33.9%), SRD-flare up (32.8%), and decompensations related to comorbidities (28%). The ICU mortality reached 14.3%. The factors associated with ICU mortality were chronic cardiac failure, invasive ventilation and admission in ICU for another reason than sepsis or SRD flare-up. The median follow-up after ICU discharge was 33.6 months. During follow-up, 109 patients died. The factors associated with long-term mortality included age, Charlson comorbidity index, and ICU admission for sepsis or SRD flare-up.The ICU mortality of patients with SRD was low. Sepsis was the first cause of admission. Cardiovascular events and comorbidities negatively impacted ICU mortality. Admission for sepsis or SRD flare-up exerted a negative effect on the long-term outcome.
34125252 Machine learning reveals the most important psychological and social variables predicting 2022 Jun There is an ongoing debate about the importance and the extent to which psychological and psychopathological factors, adverse childhood experiences, and socio-demographic characteristics are associated with the development of certain types of rheumatic disease. With the aim of contributing to knowledge on the subject, the present study uses machine learning modeling to determine the importance of 20 psychological and social variables in predicting two classes of rheumatic disease: inflammatory rheumatic and musculoskeletal diseases (RMD) (rheumatoid arthritis = RA, spondyloarthritis = SA, and Sjögren's syndrome = SS) versus non-inflammatory RMD, namely fibromyalgia = FM). A total of 165 French women with FM, RA, SA, and SS completed an inventory of personality traits, a psychopathology diagnosis questionnaire, and a fatigue/pain questionnaire. They also answered questions about adverse childhood experiences and socio-demographic characteristics. Random forest and logistic regression machine learning algorithms were used for data analysis. The main findings suggest that mistreatment during childhood ((MDA = 10.22), the agreeableness personality trait (MDA = 3.39), and somatic disorder (MDA = 3.25) are the main psychological and social predictors of the type of rheumatic disease diagnosed. The first two predictors (OR = 18.92 and OR = 6.11) are also more strongly associated with FM than with RA-SA-SS. Overall, adverse childhood experiences seem relatively more important than personality traits, psychopathological or demographic variables. The results of this study suggest that traumatic childhood experiences may lead to psychopathological disorders in adulthood, which in turn might underlie, at least in part, the development of FM. Since there are no imaging or biological markers of FM, the present findings contribute to the scientific literature offering information to help patients with FM understand their pathology. They may also provide physicians with more diagnostic information.
34976764 Characteristics and outcomes of glomerulonephritis with membranoproliferative pattern in c 2021 Nov BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare histopathologic pattern of glomerular injury with limited studies in pediatric patients. Characteristics and outcomes of children with MPGN have also remained to be further explored. METHODS: We retrospectively reviewed the clinicopathological features, genetic findings, treatments and outcomes in 17 pediatric patients pathologically diagnosed with MPGN from 2007 to 2020 in the Children's National Medical Center in China. RESULTS: Median age at disease onset was 9.9 years (IQR, 5.6-11.9 years). Most of the patients (12/17) had nephrotic range of proteinuria, and nephritic-nephrotic syndrome was the most common clinical presentation (35.2%). Secondary causes were identified in eight patients including hepatitis B virus (HBV) infection (n=4), methylmalonic acidemia (MMA, n=2), rheumatoid arthritis (RA, n=1) and Aymé-Gripp Syndrome (n=1). The nine patients with primary MPGN were further identified as immune-complex mediated MPGN (n=8), and unclassifiable MPGN (U-MGPN, n=1). Genetic analyses identified pathogenic variants of MMACHC gene in two cases of MMA and established the diagnosis for Aymé-Gripp syndrome in one case with a de novo variant of MAF gene. Comparing study between the complete or partial remission group (n=8) and non-response group (n=9) showed a significant difference in the timing of renal biopsy (P<0.05). Normal renal function was preserved in ten patients at the last follow-up. Two patients developed into end-stage renal disease (ESRD). CONCLUSIONS: Children with MPGN pattern present heterogenous clinical features. Genetic detection helps to explore underlying causes of MPGN. Early identification of the primary or secondary causes of MPGN in children is vital.
34924556 Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, o 2021 Nov 19 Several bone conditions, eg, bone cancer, osteoporosis, and rheumatoid arthritis (RA), are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and not only leads to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been believed to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here, we have addressed the disconnection between inflammation, pain, and bone erosion by using a combination of 2 monoclonal antibodies isolated from B cells of patients with RA. We have found that mice injected with B02/B09 monoclonal antibodies (mAbs) developed a long-lasting mechanical hypersensitivity that was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. By contrast, we found that inhibiting osteoclast activity and acid-sensing ion channel 3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified secretory phospholipase A2 and lysophosphatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with a secretory phospholipase A2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases such as RA.
34921994 Properties of FDA-approved small molecule protein kinase inhibitors: A 2022 update. 2022 Jan Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 68 FDA-approved therapeutic agents that target about two dozen different protein kinases and six of these drugs were approved in 2021. Of the approved drugs, twelve target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), thirteen block nonreceptor protein-tyrosine kinases, and 39 target receptor protein-tyrosine kinases. The data indicate that 58 of these drugs are prescribed for the treatment of neoplasms (49 against solid tumors including breast, lung, and colon, five against nonsolid tumors such as leukemias, and four against both solid and nonsolid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). Three drugs (baricitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases including rheumatoid arthritis. Of the 68 approved drugs, eighteen are used in the treatment of multiple diseases. The following six drugs received FDA approval in 2021 for the treatment of these specified diseases: belumosudil (graft vs. host disease), infigratinib (cholangiocarcinomas), mobocertinib and tepotinib (specific forms of non-small cell lung cancer), tivozanib (renal cell carcinoma), and trilaciclib (to decrease chemotherapy-induced myelosuppression). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and the newly approved trilaciclib. This review summarizes the physicochemical properties of all 68 FDA-approved small molecule protein kinase inhibitors including lipophilic efficiency and ligand efficiency.
34696259 Humoral Response to SARS-CoV-2 Vaccine of a Patient Receiving Methotrexate Treatment and I 2021 Oct 9 We report a case of monitoring the antibody response to the BioNTech-Pfizer vaccine of a 50-year-old female diagnosed with rheumatoid arthritis undergoing treatment with methotrexate (MTX). Antibody levels were measured 21 days after dose 1 (i.e., on the day of dose 2) and then 8, 14 and 30 days after dose 2 with Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics). Patient showed a negative result after dose 1 and had the serum sample retested using a LIAISON(®) SARS-CoV-2 TrimericS IgG assay (DiaSorin), which showed a positive result. Subsequent samples were tested using both assays. Antibody levels kept increasing but at a much slower rate than in patients not receiving any immunomodulatory therapies. Other research indicates that among patients with autoimmune diseases, those receiving disease-modifying antirheumatic drugs (DMARDs) have higher COVID-19 mortality than those treated with tumor necrosis factor inhibitors (TNFis). These results indicate the need for people with autoimmune diseases to be carefully observed following vaccinations, including testing of antibody levels, and treated as potentially at risk until the effect of vaccination is confirmed. The different available vaccines should also be tested to verify their usefulness in the case of people with autoimmune diseases and those who take different immunomodulatory medications.
34625142 JAK inhibitors for asthma. 2021 Oct Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma.
34511544 Increased MYC expression without MYC gene translocation in patients with the diffuse large 2021 Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.