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ID PMID Title PublicationDate abstract
33974078 Significance of Sjögren's syndrome and anti-cN1A antibody in myositis patients. 2022 Feb 2 OBJECTIVE: We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren's syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5'-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients. METHODS: Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0-37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-). RESULTS: . IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group. INTERPRETATION: In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS.
35283382 Acute Meningoencephalitis after COVID-19 Vaccination in an Adult Patient with Rheumatoid V 2022 May 15 We herein report a 72-year-old woman with rheumatoid vasculitis who exhibited a depressed level of consciousness after receiving the first dose of the Pfizer-BioNTech mRNA BNT162b COVID-19 vaccine and was diagnosed with meningoencephalitis. Although there was no confirmatory examination, the diagnosis was based on magnetic resonance imaging (MRI) findings and etiological assessments, including microbiological and autoimmune investigations. Both intravenous steroid pulse and gammaglobulin therapies alleviated the patient's symptoms, and the MRI findings improved. Although the efficacy of COVID-19 vaccination has been widely accepted, such neurologic complications might occur in patients with rheumatoid diseases or vasculitis syndromes.
35649411 Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotyp 2022 May 26 BACKGROUND: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases. METHODS: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. FINDINGS: Two shared clusters, CXCL10(+)CCL19(+) immune-interacting and SPARC(+)COL3A1(+) vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. CONCLUSIONS: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases. FUNDING: Grant from F. Hoffmann-La Roche (Roche) AG.
35570559 Rectal administration of Celecoxib liquid suppositories with enhanced bioavailability and 2022 May 13 BACKGROUND: Celecoxib is broadly used for the treatment of rheumatoid arthritis, however its poor bioavailability and cytotoxicity in pure form has reduced its therapeutic efficacy. This study aims to develop celecoxib liquid suppositories with improved bioavailability and reduced toxicity. METHODS: The celecoxib liquid suppositories were prepared by thoroughly mixing celecoxib, poloxamer 188 and poloxamer 407, and tween-20, respectively used as drug, polymers and surfactant, in triple distilled water using cold technique. The developed liquid suppositories were characterized in terms of their gelation temperature, gelation time, and gel strength. Moreover, the muco-adhesive force was determined for the suppositories. The release behavior of the liquid suppositories was investigated in distilled water and compared with drug suspension. Furthermore, pharmacokinetics and morphological studies were carried out in rats after rectal administration of the celecoxib liquid suppository compared with drug suspension. RESULTS: Poloxamer 188 and Tween-20 concentrations have significantly reduced the gelation temperature and time, however, the gel strength and bio-adhesive force were significantly enhanced. The concentration of celecoxib has no significant effect on the properties of liquid suppositories. A significantly enhanced and potentially sustained drug release was observed from the celecoxib liquid suppositories as compared with the drug suspension. The optimized formulation was easy to administer rectally because it quickly forms gel upon insertion into the body due to a suitable gelation temperature of about 31.7 0C. After rectal administration in rats, the celecoxib liquid suppository gave a significantly increased pharmacokinetic profile including enhanced plasma concentration and 9.7 fold improved area under the curve (AUC) compared to the drug suspension. Additionally, the morphology study exhibited no toxicity to the rectal tissue, no signs of irritation, or injury after the application of suppository. However, severe rectal tissue toxicity and irritation was observed in the suspension treated rectum. CONCLUSIONS: It can be concluded that the liquid suppository system may significantly enhance the solubilization and bio-availability of sparingly water-soluble drugs as evident in the case of celecoxib with no toxicity at the site of application.
35554562 Systemic Chronic Diseases Coexist with and Affect Locomotive Syndrome: The Nagahama Study. 2022 May 12 OBJECTIVES: The concept of locomotive syndrome was proposed to highlight older adults who require nursing care services due to the malfunctioning of their locomotive organs. With the coming of a super-aging society, there is a growing need to understand relation between systemic chronic diseases and locomotive syndrome. METHODS: We analyzed the second-visit dataset of the Nagahama Study. The association analysis was performed to identify the chronic diseases that were risk factors associated with the occurrence and the progression of locomotive syndrome in both the cross-sectional and longitudinal studies. RESULTS: Hypertension, stroke, coronary heart disease, rheumatoid arthritis, chronic renal failure, osteoporosis, anemia, and gastroesophageal reflux disease were independently correlated with locomotive syndrome through the deterioration of body pain, social activity, and cognitive function in the cross-sectional study. Multiple chronic diseases had additive effects and significantly increased the risk of locomotive syndrome. In the longitudinal study, osteoporosis and kidney disease were significantly correlated with the worsening of the total GLFS-25 score. CONCLUSIONS: Locomotive syndrome coexisted with various systemic chronic diseases, especially cardiovascular diseases. Osteoporosis and kidney disease were significantly correlated with the progression of locomotive dysfunction. The management of various chronic diseases may be useful to prevent locomotive syndrome and vice versa.
35467520 Advancing Patient-Partnered Research: Empowerment, Innovation and Evolution. 2022 Apr From the perspective of patient partners, the Ontario SPOR SUPPORT Unit Engaging Multi-stakeholders for Patient Oriented-research Wider Effects and Reach Awards have facilitated successful patient-partnered research projects, which, in turn, have led to an evolution in patient partnerships and engagement strategies. The 15 projects profiled in this special issue point to the beneficial impacts of patient-partnered research.
35370923 Evaluation of the Psychometric Properties of Jebsen Taylor Hand Function Test (JTHFT) in I 2022 INTRODUCTION: The Jebsen Taylor Hand Function Test (JTHFT) is a non-diagnostic assessment scale for hand and upper limb dexterity that is commonly used in various countries around the world for diseases, such as muscular dystrophy, stroke, spinal cord injury, Parkinson, carpal tunnel syndrome, and rheumatoid arthritis. This study aimed to evaluate the psychometric properties of the JTHFT in Italian adults with Multiple Sclerosis (MS). MATERIALS AND METHODS: The test's internal consistency was evaluated with Cronbach's alpha, whereas its concurrent validity was evaluated by comparing the JTHFT with the Health Assessment Questionnaire (HAQ) and by calculating Pearson's correlation coefficient. RESULTS: The JTHFT was administered to 29 Italians with MS. The Cronbach's alpha showed that the nondominant hand has a value of 0.76 and 0.91 for the dominant hand. Pearson's correlation coefficient showed significant correlations between JTHFT and HAQ. DISCUSSION: The JTHFT is a reliable tool to evaluate the functionality of the upper limb and hand in patients with MS. This tool is useful for testing the effectiveness of a treatment in various diseases. The results obtained in this study are coherent with previous studies that are conducted in populations with different diseases. In particular, the correlation between JTHFT and HAQ showed that a disability related to the upper limbs can often have repercussions, not only on activities of daily living, but also on walking. Based on this correlation, the motor deficits that emerged may be linked to a brain marrow disease rather than a spinal disease, even if an essential deepening can confirm this hypothesis.
35187874 Identification of venular capillary remodelling: a possible link to the development of per 2022 Feb PURPOSE: The present study measured changes in arteriolar and venular capillary flow and structure in the gingival tissues during the development of plaque-induced gingival inflammation by combining dynamic optical coherence tomography (OCT), laser perfusion, and capillaroscopic video imaging. METHODS: Gingival inflammation was induced in 21 healthy volunteers over a 3-week period. Gingival blood flow and capillary morphology were measured by dynamic OCT, laser perfusion imaging, and capillaroscopy, including a baseline assessment of capillary glycocalyx thickness. Venular capillary flow was estimated by analysis of the perfusion images and mean blood velocity/acceleration in the capillaroscopic images. Readings were recorded at baseline and weekly over the 3 weeks of plaque accumulation and 2 weeks after brushing was resumed. RESULTS: Perfusion imaging demonstrated a significant reduction of gingival blood flow after 1 and 2 weeks of plaque accumulation (P<0.05), but by 3 weeks of plaque accumulation there was a more mixed picture, with reduced flow in some participants and increased flow in others. Participants with reduced flux at 3 weeks also demonstrated venular-type flow as determined by perfusion images and evidence of the development of venular capillaries as assessed by the velocity/acceleration ratio in capillaroscopic images. After brushing resumed, these venular capillaries were broken down and replaced by arteriolar capillaries. CONCLUSIONS: After 3 weeks of plaque accumulation, there was wide variation in microvascular reactions between the participants. Reduced capillary flow was associated with the development of venular capillaries in some individuals. This is noteworthy, as an early increase in venous capillaries is a key vascular feature of cardiovascular disease, psoriasis, Sjögren syndrome, and rheumatoid arthritis-diseases with a significant association with the development of severe gingival inflammation, which leads to periodontitis. Future investigations of microvascular changes in gingival inflammation might benefit from accurate capillary flow velocity measurements to assess the development of venular capillaries.
35135427 The Prevalence and Risk Factors for Trigger Digits in a Random Sampling of a Japanese Popu 2022 Feb Background: Trigger digit(s) (TD) is one of the most common disorders of the hand in the elderly population. The aim of this study is to determine the prevalence and identify the risk factors for TD in an elderly Japanese population. Methods: We randomly sampled 1,297 subjects between the ages of 50 and 89 years from the population registry of a town in Japan. About 413 subjects agreed to participate in the study, and all were examined for the presence of TD. Subjects were divided into three groups namely history of treatment for TD in the past (PTD), current evidence of TD (CTD) or both (BTD). The prevalence of TD was weighted by age according to the composition of the Japanese population. Age, female gender, obesity, hard manual work, exposure to vibration tools, sports activity, smoking, alcohol, wrist fracture, hypertension, hypothyroidism, diabetes mellitus, rheumatoid arthritis and carpal tunnel syndrome were assessed as risk factors for TD using univariate and multivariate logistic regression analysis. Results: Forty subjects had TD. This included 18, 19 and 3 subjects with PTD, CTD and BTD, respectively. The weighted prevalence of TD was 9.7% (female, 14.3%; male, 4.4%) in the Japanese population aged 50-89 years. Age 70-79 and female gender were identified as risk factors for TD. Conclusions: The random sampling of a Japanese population registry between the ages of 50 and 89 years revealed the prevalence of TD as 9.7% and identified age between 70 and 79 and female gender as risk factors for developing TD. Level of Evidence: Level II (Therapeutic).
35133890 Current Knowledge of Biologics in Treatment of Noninfectious Uveitis. 2022 Apr The arena of uveitis deals with a number of entities, which can be infectious or immune mediated. Noninfectious uveitis (NIU) has been managed with corticosteroids and immunosuppressives. However, their prolonged use has side effects limiting clinical utility in the long run. Improved knowledge regarding pathogenesis of uveitis and associated systemic disease has led to a new epoch in the development of treatment strategies, of which biologics are the recent ones. Biologics revolutionized the management of NIU especially uveitis associated with spondyloarthropathy and refractory uveitis. They target inflammation at a molecular level with less side effects. The most widely used are tumor necrosis factor-alpha inhibitors (infliximab and adalimumab). Other drugs include anti-CD20 inhibitors (rituximab), interleukin-6R-inhibitor (tocilizumab), Interleukin-1R-inhibitor (anakinra), Iinterleukin-2-inhibitor (daclizumab), and the list is further increasing. New advances in biologics are the biosimilar molecules, which are biological products that are highly similar to the reference product, and they include Infimab (biosimilar of infliximab), Exemptia or Adfrar (biosimilar of adalimumab), and Intacept or Etacept (biosimilar of etanercept). Other group of biologics are Janus Associated Kinase inhibitors (JAK-inhibitors), which are long-term oral treatment options of rheumatoid arthritis. They inhibit JAKs, which cause activation of signal transducer and activator of transcription (STAT) proteins, and initiate transcription of inflammatory genes. Many inflammatory cytokines that are implicated in pathogenesis of ocular inflammation are known to utilize the JAK/STAT-signaling pathway, including interleukin-2 (IL-2) and IL-6. Thus, biologics are the future of uveitis treatment with promising results. This article aims to summarize the current knowledge on biologics and their clinical utility in the management of NIU.
35131063 ARDS With Pneumothorax in a Young Adult. 2022 Feb A 19-year-old, previously healthy man presented with 3 days of cough, high-grade fevers (40 °C), and dyspnea. Apart from a resolved history of seizures not requiring medications, he had no medical or surgical history. He had no known drug allergies. He took montelukast for allergies and trimethoprim-sulfamethoxazole (TMP-SMX) for 2 weeks before admission for acne, but no other medications, including over-the-counter medications and supplements. He had animal exposures to a new puppy and a friend's bird. He had no history of smoking, vaping, or recreational drug use. His paternal grandmother had rheumatoid arthritis.
35037353 Patient knowledge of gut microbiota and acceptability of fecal microbiota transplantation 2022 Jan 17 BACKGROUND: Fecal microbiota transplantation (FMT) is now evaluated in various diseases. However, large-scale population treatment may encounter feasibility issues in terms of acceptance. We aim to evaluate patient knowledge of gut microbiota and the acceptability of FMT in various diseases. METHODS: Patients of Carenity's French online community were invited by email to participate in a questionnaire. The following parameters were assessed: patient's principal illness and duration, demographic data, therapeutics, dietary habits, knowledge of gut microbiota, probiotics and FMT, and its acceptability. KEY RESULTS: In total, 877 patients participated in the online questionnaire: 156 with inflammatory bowel disease (17.8%), 127 with rheumatoid arthritis (14.5%), 222 with ankylosing spondylitis (25.3%), 52 with lupus (5.9%), 64 with psoriasis (7.3%), 61 with obesity (7%), and 195 with type 2 diabetes (22.2%). Characteristics of participating patients were similar to those of the entire cohort (n = 23084). Overall, 47.1% (n = 413/877) of patients knew what the microbiota is with no difference among diseases. Knowledge was reported to be developed by patients themselves (203/413; 49.2%) without involving a healthcare professional. If proposed by a healthcare professional, 37.2% (326/877) reported being interested or very interested in undergoing FMT. Factors associated with good acceptability of FMT were the male sex (OR: 1.63, CI95% [1.14 to 2.32]), previous knowledge of FMT (OR: 4.16, CI95% [2.92 to 5.96]), and previous knowledge of gut microbiota (OR: 1.54, CI95% [1.05 to 2.24]). CONCLUSION AND INFERENCES: Knowledge of gut microbiota is still limited in patients' communities and mainly developed by patients themselves, impacting FMT acceptability.
34731869 Infective Necrotizing Scleritis After XEN Gel Stent With Mitomycin-C. 2022 Feb 1 PURPOSE: The purpose of this study was to report a case of infective necrotizing scleritis following XEN Gel Stent with mitomycin-C. METHODS: Case report. This is a case report of a 68-year-old woman. RESULTS: XEN Gel Stent glaucoma surgery enhanced with mitomycin-C 0.04% and combined with cataract surgery was performed at a regional center to manage the patient's primary open-angle glaucoma. Past medical history was significant for rheumatoid arthritis requiring treatment with methotrexate and adalimumab. Periocular pain and swelling developed 14 months after the initial operation, followed by a rapid deterioration of visual acuity to 20/60, intraocular pressure of 4 mm Hg, and worsening pain 5 months later. On initial presentation to Sydney Eye Hospital, 180 degrees of scleral necrosis was evident with a moderate anterior segment inflammatory reaction and a large temporal choroidal effusion due to hypotony. Empirical hourly topical ofloxacin and cephalothin 5% drops, with oral moxifloxacin, were initiated. Conjunctival swab grew Staphylococcus aureus and Staphylococcus lugdunensis. Significant clinical improvement occurred, but the XEN Gel Stent became exposed after 9 days of treatment with worsening hypotony. Urgent surgical revision was performed to remove the XEN Gel Stent and apply a tutoplast plug with overlying amniotic membrane graft. Intraocular pressure gradually improved over 6 weeks to 15 mm Hg with reversal of hypotonous changes, and visual acuity stabilized at 20/40. CONCLUSIONS: To our knowledge, this is the first reported case of necrotizing scleritis following XEN Gel Stent insertion. It is a reminder that infection should always be the primary differential diagnosis in patients with surgical-induced necrotizing scleritis.
34453532 The immunological significance of tumor necrosis factor receptor-associated factors (TRAFs 2022 Jan 1 The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular signaling adaptors and control diverse signaling pathways mediated not only by the TNFR superfamily and the Toll-like receptor/IL-1 receptor superfamily but also by unconventional cytokine receptors such as IL-6 and IL-17 receptors. There are seven family members, TRAF1 to TRAF7, in mammals. Exaggerated immune responses induced through TRAF signaling downstream of these receptors often lead to inflammatory and autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoinflammatory syndromes, and thus those signals are major targets for therapeutic intervention. For this reason, it has been very important to understand signaling mechanisms regulated by TRAFs that greatly impact on life/death decisions and the activation, differentiation and survival of cells of the innate and adaptive immune systems. Accumulating evidence suggests that dysregulated cellular expression and/or signaling of TRAFs causes overproduction of pro-inflammatory cytokines, which facilitates aberrant activation of immune cells. In this review, I will explain the structural and functional aspects that are responsible for the cellular activity and disease outcomes of TRAFs, and summarize the findings of recent studies on TRAFs in terms of how individual TRAF family molecules regulate biological and disease processes in the body in both positive and negative ways. This review also discusses how TRAF mutations contribute to human disease.
35637376 Filgotinib: A Clinical Pharmacology Review. 2022 May 31 Filgotinib (GS-6034, formerly GLPG0634; Jyseleca(®)) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK-signal transducer and activator of transcription pathway, which differ from those inhibited by JAK2 or JAK3. Filgotinib is absorbed extensively and rapidly after oral dosing and is metabolized by carboxylesterase isoform 2 to form its primary active metabolite, GS-829845. The primary metabolite has a similar JAK1 selectivity profile but reduced activity (by 10-fold) and increased systemic exposure (approximately 16- to 20-fold) compared with the parent compound. Both the parent and the metabolite demonstrate low binding to plasma proteins in humans (< 60%). Systemic exposures of filgotinib and its primary metabolite increase dose proportionally over a 50- to 200-mg once-daily dose range. Food does not affect the pharmacokinetics of filgotinib. Consistent with their terminal elimination half-lives (4.9-10.7 h for filgotinib and 19.6-27.3 h for the primary metabolite), steady state in plasma is reached by day 2 for filgotinib and day 4 for its metabolite. Filgotinib is mainly eliminated in the urine as the metabolite (> 80%). Intrinsic factors such as age, sex, race, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite. Filgotinib has a low drug-drug interaction potential, without clinically significant interactions with commonly coadministered medications in patients with inflammatory diseases. Both filgotinib and its primary metabolite are substrates of P-glycoprotein (P-gp); however, coadministration with P-gp inhibitors and inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment. Neither filgotinib nor its primary metabolite affect the corrected QT interval (calculated using Fridericia's correction formula). Filgotinib is approved for the treatment of rheumatoid arthritis and ulcerative colitis in Europe, the UK, and Japan.
35359225 Rheumatic Diseases in Reproductive Age-the Possibilities and the Risks. 2022 Mar 31 The most common systemic connective tissue diseases (CTD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis (SSc), and Sjögren's syndrome (SjS), affect many women of reproductive age. These diseases may strongly impact the course of pregnancy and increase the risk factors of incompatibility. A literature search was done on MEDLINE, PubMed, and Google Scholar in 2011-2021. The analysis included meta-analysis, randomized control trials, prospective and retrospective studies, and systematic reviews. The literature search allowed us to form conclusions and underline recommendations regarding pregnancy's risk and treatment possibilities in the course of rheumatic disease. Optimal control of CTD activity should be reached at least 6 months before conception. High-risk pregnancies are often accompanied by maternal-placental syndrome, which manifests as preeclampsia, eclampsia, fetal growth restriction, and prematurity. The flare of rheumatic disease can coexist with obstetrical complications, and differential diagnosis can be difficult. Medications that do not influence the risk of fetus complications should be applied before and during pregnancy. Teratogenic drugs (e.g., methotrexate, leflunomide, cyclophosphamide) must be withdrawn before pregnancy. Conventional medications such as hydroxychloroquine, sulfasalazine, colchicine, and the TNFα inhibitor certolizumab can be used safely at any stage of pregnancy. Corticosteroids should be tapered, and other biologics should be avoided due to teratogenicity or carefully administered due to the impact on the fetal immune system. Distinguishing between disease flare and obstetrical complications can be difficult in clinical practice; however, some clinical symptoms and serological markers can be helpful in the differential diagnosis.
35508810 Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases. 2022 Jun Sphingosine 1-phosphate (S1P), which acts via G protein-coupled S1P receptors (S1PRs), is a bioactive lipid essential for vascular integrity and lymphocyte trafficking. The S1P-S1PR signalling axis is a key component of the inflammatory response in autoimmune rheumatic diseases. Several drugs that target S1PRs have been approved for the treatment of multiple sclerosis and inflammatory bowel disease and are under clinical testing for patients with systemic lupus erythematosus (SLE). Preclinical studies support the hypothesis that targeting the S1P-S1PR axis would be beneficial to patients with SLE, rheumatoid arthritis (RA) and systemic sclerosis (SSc) by reducing pathological inflammation. Whereas most preclinical research and development efforts are focused on reducing lymphocyte trafficking, protective effects of circulating S1P on endothelial S1PRs, which maintain the vascular barrier and enable blood circulation while dampening leukocyte extravasation, have been largely overlooked. In this Review, we take a holistic view of S1P-S1PR signalling in lymphocyte and vascular pathobiology. We focus on the potential of S1PR modulators for the treatment of SLE, RA and SSc and summarize the rationale, pathobiology and evidence from preclinical models and clinical studies. Improved understanding of S1P pathobiology in autoimmune rheumatic diseases and S1PR therapeutic modulation is anticipated to lead to efficacious and safer management of these diseases.
35431536 Could anakinra outmatch dexamethasone/tocilizumab in COVID-19? 2022 The hyperinflammatory state leading to an aberrant cytokine production, culminating in acute respiratory distress syndrome, sepsis and multi-organ dysfunction contribute much to the pathophysiologies of severe COVID-19. These severe patients have similar clinical manifestations with patients suffering from certain auto-inflammatory disorders and cytokine storm syndromes. Interestingly, anakinra (blocking both IL-1α and IL-1β) has shown promises in treating these patients with hyperinflammatory disorders, sepsis with multiorgan failures. Another inflammasome, AIM2, involved in production of IL-1 has also been found to be implicated in COVID-19. IL-1β, a known procoagulant, causes induction of tissue factor with increasing vascular endothelial permeability loss ensuing in hypercoagulability-one of the cardinal features of the disease. Hence, anakinra a 17kD recombinant human IL-1 receptor antagonist, used widely in Rheumatoid Arthritis treatments might prove efficacious in attenuating the hyperinflammatory state of the disease. Indeed, some of the controlled clinical trials have shown anakinra to effectively decrease mortality and hospital stay. Targeted cytokine blocking are always preferable in comparison with non-specific blocking (steroids) as it is more restrained with the chances of dampening of systemic immune system being much less. Early cell death and neutrophil migration have been one of the pivotal events in COVID-19 pathogenesis. Hence, suPAR levels which measures IL-1α (necroptosis) and S100A8/A9 (neutrophil migration) can perhaps be a good early biomarker predicting the disease progression. Lastly and importantly, as the vaccines are raised against spike protein and the different variants of concern are known to evade the neutralizing antibodies by varying degrees, it will be deserving to assess anakinra, against the variants of concern as an immunomodulatory drug.
35303257 Thoracic Involvement in Systemic Autoimmune Rheumatic Diseases: Pathogenesis and Managemen 2022 Mar 18 Thoracic involvement is one of the main determinants of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs), with different prevalence and manifestations according to the underlying disease. Interstitial lung disease (ILD) is the most common pulmonary complication, particularly in patients with systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). Other thoracic manifestations include pulmonary arterial hypertension (PAH), mostly in patients with SSc, airway disease, mainly in RA, and pleural involvement, which is common in systemic lupus erythematosus and RA, but rare in other ARDs.In this review, we summarize and critically discuss the current knowledge on thoracic involvement in ARDs, with emphasis on disease pathogenesis and management. Immunosuppression is the mainstay of therapy, particularly for ARDs-ILD, but it should be reserved to patients with clinically significant disease or at risk of progressive disease. Therefore, a thorough, multidisciplinary assessment to determine disease activity and degree of impairment is required to optimize patient management. Nevertheless, the management of thoracic involvement-particularly ILD-is challenging due to the heterogeneity of disease pathogenesis, the variety of patterns of interstitial pneumonia and the paucity of randomized controlled clinical trials of pharmacological intervention. Further studies are needed to better understand the pathogenesis of these conditions, which in turn is instrumental to the development of more efficacious therapies.
35266012 P2X7 receptor knockdown suppresses osteoclast differentiation by inhibiting autophagy and 2022 May Bone is continuously remodeled in a dynamic process maintained by osteoclasts and osteoblasts, and imbalances in the relative activities of these cell types can cause various pathological conditions, including rheumatoid arthritis and osteoporosis. Osteoclasts are multinucleated cells that serve an important role in regulating the development of osteoporosis. Furthermore, P2X7 receptor activation has a vital role in physiological and pathological reactions in bone, including bone disease. Therefore, the present study aimed to investigate the effect of P2X7 receptor on osteoclast differentiation and to explore the underlying molecular mechanism by western blotting and tartrate‑resistant acid phosphatase staining. The results indicated that the expression levels of P2X7 receptor and intracellular Ca2+ concentration levels were very high in mature osteoclasts. Furthermore, P2X7 receptor overexpression increased the number of multinucleated osteoclasts and the expression of osteoclastogenesis‑related proteins. P2X7 receptor overexpression was also associated with downstream activation of Ca(2+)/calcineurin/nuclear factor of activated T cells c1 (NFATc1) signaling and increased expression of autophagy‑related proteins during osteoclast differentiation. By contrast, knockdown of P2X7 receptor exerted the opposite effects. Notably, FK506 (a Ca(2+)/calcineurin/NFATc1 signaling inhibitor) abrogated P2X7 receptor overexpression‑induced osteoclast differentiation and activation of autophagy. Moreover, 3‑MA (an autophagy inhibitor) significantly suppressed P2X7 receptor overexpression‑induced osteoclast differentiation. In conclusion, P2X7 receptor knockdown may suppress osteoclast differentiation by modulating autophagy and the Ca(2+)/calcineurin/NFATc1 signaling pathway.