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ID PMID Title PublicationDate abstract
30864505 Biosimilars of Adalimumab in Inflammatory Bowel Disease: Are we Ready for that? 2019 Biosimilars present a considerable potential to reduce costs related to clinical management allowing health-care providers to reinvest this money, leading to a wider access to an effective biological treatment with monoclonal antibodies (mAb). Infliximab biosimilars have already been incorporated in daily clinical practice and are currently used in all indications for which the reference product (RP) was approved. Areas covered: In the next few years, also adalimumab biosimilars will become available for the treatment of inflammatory bowel disease (IBD). In fact, several of them (ABP501, BI 695501, GP2017, and SB5) have been approved by the European Medicines Agency (EMA) with the same indications of the reference product (Humira ®). Initial preclinical data proved a strong similarity between all biosimilars and the RP. Moreover, phase 3 studies in rheumatoid arthritis and psoriasis showed no differences in terms of efficacy, safety, and immunogenicity. Data on IBD patients are urgently needed. Expert opinion: Biosimilars of adalimumab showed equivalent clinical efficacy to the RP in other immunemediated diseases. However, defining the ideal patient's profile to receive or to be switched to a biosimilar, choosing one biosimilar vs. another, or cross-switching among biosimilars, will become the next challenge in IBD.
30773908 Identification of potential CRAC channel inhibitors: Pharmacophore mapping, 3D-QSAR modell 2019 Feb Upregulation of store-operated Ca(2+) influx via ORAI1, an integral component of the CRAC channel, is responsible for abnormal cytokine release in active rheumatoid arthritis, and therefore ORAI1 has been proposed as an attractive molecular target. In this study, we attempted to predict the mechanical insights of ORAI1 inhibitors through pharmacophore modelling, 3D-QSAR, molecular docking and free energy analysis. Various hypotheses of pharmacophores were generated and from that, a pharmacophore hypothesis with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic rings (AADRR) resulted in a statistically significant 3D-QSAR model (r(2) = 0.84 and q(2) = 0.74). We believe that the obtained statistical model is a reliable QSAR model for the diverse dataset of inhibitors against the IL-2 production assay. The visualization of contours in active and inactive compounds generated from the 3D-QSAR models and molecular docking studies revealed major interaction with GLN108, HIS113 and ASP114, and interestingly, these residues are located near the Ca(2+) selectivity filter region. Free energy binding analysis revealed that Coulomb energy, van der Waals energy and non-polar solvation terms are more favourable for ligand binding. Thus, the present study provides the physical and chemical requirements for the development of novel ORAI1 inhibitors with improved biological activity.
30771625 Mediastinal, retroperitoneal, and subcutaneous emphysema due to sigmoid colon penetration: 2019 INTRODUCTION: Mediastinal and subcutaneous emphysema usually result from spontaneous rupture of the alveolar wall. We present an extremely rare case of massive mediastinal, retroperitoneal, and subcutaneous emphysema due to the penetration of the colon into the mesentery. PRESENTATION OF CASE: A 57-year-old man presented to our institution with a history of chest pain. The patient's medical history included malignant rheumatoid arthritis during the use of steroids and an immunosuppressive agent. The patient had no signs of peritoneal irritation or abdominal pain. A chest radiography revealed subcutaneous emphysema of the neck, mediastinal emphysema, as well as subdiaphragmatic free air. Computed tomography showed extensive retroperitoneal, mediastinal, and mesenteric emphysema of the sigmoid colon without pneumothorax. Diagnostic laparoscopy was performed and revealed perforation into the sigmoid mesentery. Segmental resection of the sigmoid colon and end-colostomy were performed. The diverticulum was communicating with the outside of the mesentery via the mesentery. The mediastinal emphysema disappeared a few days after the surgery. DISCUSSION: Colonic perforation generally results in free perforation. Colonic gas may spread via various anatomical pathways when perforation of the colon occurs in the retroperitoneum; thus, diverse atypical clinical symptoms may be present. Signs of peritoneal irritation can be hidden in cases of retroperitoneal colonic perforation. The atypical manifestation of a retroperitoneal colonic perforation can cause difficulties in making a diagnosis. CONCLUSIONS: Massive mediastinal and retroperitoneum emphysema are rare signs of colonic perforation. Emergency laparotomy should be considered in colonic penetration of the diverticulitis where the emphysema expands to the mediastinum extensively.
30766739 Degradation Characteristics of a Novel PAF Receptor Antagonist, SY0916, in Aqueous Solutio 2019 SY0916 has been proven to be a potent treatment agent against rheumatoid arthritis in preclinical studies and has been shown to be safe in phase I clinical trials. However, SY0916 is unstable in water, which is frequently used in pharmaceutical development processes. The degradation behaviour and stability of SY0916 in aqueous solutions were investigated at different pH levels, periods of time, and temperatures. Two degradation products (DPs) were successfully separated and characterized by liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS), liquid chromatography coupled to nuclear magnetic resonance with solid phase extraction (LC-SPE-NMR), and nuclear magnetic resonance (NMR). SY0916 decomposed to its α,β-unsaturated ketone in protonic solvents, and the α,β-unsaturated ketone further transformed into its alcohol form through a conjugate addition reaction in aqueous media. The results of this study indicate that the pH of the buffer solutions should be maintained between 3.0 and 3.6 for maximum SY0916 stability. Factors that affect degradation should be carefully controlled to mitigate or avoid drug decay.
30666796 Targeted inhibition of histone deacetylase 6 in inflammatory diseases. 2019 Mar Targeting epigenetic modification of gene expression represents a promising new approach under investigation for the treatment of inflammatory diseases. Accumulating evidence suggests that epigenetic mechanisms, such as histone modification, play a crucial role in a number of inflammatory diseases, including rheumatoid arthritis, asthma, and contact hypersensitivity. Consistent with this role, histone deacetylase (HDAC) inhibitors have shown efficacy in the treatment of inflammatory diseases. In particular, selective inhibitors of HDAC6, a cytoplasmic member of the HDAC family that contains two deacetylase domains, are under investigation as a potential treatment strategy for inflammatory diseases due to their ability to regulate inflammatory cells and cytokines. Here, we review recent findings highlighting the critical roles of HDAC6 in a variety of inflammatory diseases, and discuss the therapeutic potential of HDAC6 inhibitors in these settings.
30643542 Practical guidance for the management of inflammatory bowel disease in patients with cance 2019 Clinicians involved in the treatment of inflammatory bowel disease (IBD) increasingly come across patients with current or previous history of malignancies. With increasing and earlier use of immunosuppression and biologics in IBD patients, the question arises whether these treatments further increase the risk of new or recurrent cancers. A number of population-based observational studies have now reported the odds of development of new or recurrent cancers with thiopurines and antitumour necrosis factors (anti-TNFs). These data combined with data arising from treatment registries from other immune disorders such as rheumatoid arthritis are providing evidence of relative risks and safety profiles of these agents in the setting of active or prior cancer. Data from transplant literature give an indication for providing a drug-holiday period in patients with treated cancers. The risks of the treatment should be considered alongside the risk associated with withholding these effective treatments in patients with active IBD. In this review, we aim to summarize the current evidence in this area and provide a practical guidance.
30635081 Inflammatory response and its relation to sphingolipid metabolism proteins: Chaperones as 2019 Lysosome is the organelle responsible for breaking down macromolecules to maintain homeostasis and to fight infection. The disruption of normal lysosomal function due to mutations in the sphingolipid metabolism proteins leads to a class of lysosomal storage diseases (LSDs). Defective autophagy and activation of inflammation are observed in most LSDs. The crosstalk between these key metabolic pathways suggests that therapeutic approaches used in the treatment of LSDs may provide anti-inflammatory therapies against chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease. Here, we review the role of sphingolipids in the inflammatory response and build a protein-protein interaction network for proteins related with sphingolipid metabolism and inflammation to identify key interaction partners for the crosstalk between sphingolipids and inflammation. In addition, we present an overview of LSDs in relation with sphingolipids and inflammation, and review the pharmacological chaperones identified for these diseases.
30433838 JAK-inhibitors in dermatology: current evidence and future applications. 2019 Nov The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is a ubiquitous intracellular signaling network. Selective JAK-inhibitors have anti-inflammatory properties and have been approved in many countries for the treatment of rheumatoid arthritis (tofacitinib, baricitinib) and myelofibrosis or polycythemia vera (ruxolitinib). The aim of the publication was to summarize and critically analyze the efficacy and safety of JAK-inhibitors in skin diseases, such as psoriasis, alopecia areata, atopic dermatitis and vitiligo. Databases PubMed, Scopus and EBSCO were searched. After exclusions, 17 articles were analyzed (11 randomized clinical trials, 4 case reports, 1 retrospective study of a case series and 1 nonrandomized pilot study). The strongest evidence of JAK-inhibitor efficacy was established for treatment of psoriasis. Additionally, data are available on the potential efficacy of JAK-inhibitors in alopecia areata, atopic dermatitis and vitiligo. Mostly, JAK-inhibitors are used orally. However, there are studies showing efficacy of topical administration of this group of drugs in psoriasis and vitiligo. Further research is needed, especially the head-to-head comparison studies with JAK-inhibitors and current therapeutic methods to verify the superiority of this new group of drugs in dermatological diseases.
32038189 Contributions of Interleukin-1 Receptor Signaling in Traumatic Brain Injury. 2019 Traumatic brain injury (TBI) in various forms affects millions in the United States annually. There are currently no FDA-approved therapies for acute injury or the chronic comorbidities associated with TBI. Acute phases of TBI are characterized by profound neuroinflammation, a process that stimulates the generation and release of proinflammatory cytokines including interleukin-1α (IL-1α) and IL-1β. Both forms of IL-1 initiate signaling by binding with IL-1 receptor type 1 (IL-1R1), a receptor with a natural, endogenous antagonist dubbed IL-1 receptor antagonist (IL-1Ra). The recombinant form of IL-1Ra has gained FDA approval for inflammatory conditions such as rheumatoid arthritis, prompting interest in repurposing these pharmacotherapies for other inflammatory diseases/injury states including TBI. This review summarizes the currently available preclinical and clinical literature regarding the therapeutic potential of inhibiting IL-1-mediated signaling in the context of TBI. Additionally, we propose specific research areas that would provide a greater understanding of the role of IL-1 signaling in TBI and how these data may be beneficial for the development of IL-1-targeted therapies, ushering in the first FDA-approved pharmacotherapy for acute TBI.
31646017 Iguratimod: a valuable remedy from the Asia Pacific region for ameliorating autoimmune dis 2019 Autoimmune diseases are affected by complex pathophysiology involving several cell types, cytokines, antibodies, and mimicking factors. Different drugs are used to ameliorate these autoimmune reactions, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antiantibodies, and small molecular drugs (DMARDs), and they are clinically in vogue for diseases such as rheumatoid arthritis (RA). Nevertheless, low cost-effectiveness, reduced efficacy, adverse effects, and patient nonresponse are unappealing factors driving the development of new drugs such as iguratimod. Iguratimod is primarily used to ameliorate RA in Japanese and Chinese clinics. However, its efficacy against other autoimmune ailments is also under intense investigation, and the number of investigations is becoming increasingly larger with each passing day. The articular structure comprises synovium, ligaments, and bone. The latter is more complex than the others since it regulates blood cells and autoimmunity in addition to providing skeletal support to the body. Therefore, its protection is also of prime importance in RA and other autoimmune diseases. Herein, we have highlighted the role of iguratimod in autoimmune diseases and bone protection. We suggest that iguratimod's unique mode of action compared with that of other DMARDs and its good patient response makes it a suitable antirheumatic and bone-protecting drug.
31522830 Inhaled Janus Kinase (JAK) inhibitors for the treatment of asthma. 2019 Oct 15 Multiple asthma-relevant cytokines including IL-4, IL-5, IL-13, and TSLP depend upon JAKs for signaling. JAK inhibition may, therefore, offer a novel intervention strategy for patients with disease refractory to current standards of care. Multiple systemically delivered JAK inhibitors have been approved for human use or are under clinical evaluation in autoimmune diseases such as rheumatoid arthritis. However, the on-target side effect profiles of these agents are likely not tolerable for many asthmatic patients. Limiting JAK inhibition to the lung is expected to improve therapeutic index relative to systemic inhibition. Thus, inhaled JAK inhibitors with lung-restricted exposure are of high interest as potential treatments for asthma.
31942434 Ocular syphilis mimicking Vogt-Koyanagi-Harada disease. 2019 Oct The study aimed to present a case of ocular syphilis mimicking Vogt-Koyanagi-Harada (VKH) disease. This is an observational case report. A 59-year-old female with Sicca syndrome and rheumatoid arthritis presented to the ophthalmologic department with blurred vision of the right eye for 5 days accompanied by color sensation loss in both eyes. Bilateral disc hyperemia and serous retinal detachment at the posterior pole were noted in her both eyes by fundus examination. Fluorescein angiography revealed bilateral late dye leakage from the disc and posterior choroid. Optical coherence tomography showed bilateral subretinal fluid and choroidal thickening. The impression of her condition was VKH disease initially. However, she was later diagnosed with bilateral ocular syphilis with optic neuritis which was proved by laboratory data. After appropriate antimicrobial agent treatment, her best-corrected visual acuity, serous retinal detachment, and disc hyperemia improved. There was no recurrent intraocular inflammation even without systemic steroid or immunosuppressive therapy control during the following 1 year. Ocular syphilis can mimic many other ocular inflammatory diseases including VKH disease. It is necessary to differentiate infectious causes from inflammatory origins due to the substantially different treatment and prognosis.
31863819 The past, present and future perspectives of matrix metalloproteinase inhibitors. 2020 Mar Matrix metalloproteinases (MMPs) are a large family of enzymes that degrade the extracellular matrix (ECM). Under pathologic conditions, overexpression of MMPs or insufficient control by tissue inhibitors of MMPs (TIMPs) results in the dysregulation of tissue remodeling and causes a variety of diseases such as encephalomyelitis, rheumatoid arthritis, Alzheimer's disease and tumors. Therefore, the high affinity of MMPs for biomolecules renders them attractive targets for inhibition when homeostasis breaks down in the ECM. There are 4 generations of MMP inhibitors (MMPIs), ranging from small molecules or peptides to antibodies and protein-engineered inhibitors of metalloproteinase. Although a plethora of MMPIs has been synthesized, most of them have failed in clinical trials or are still in the laboratory stage of development. The present review summarizes the development of MMPIs, their associated problems and discusses future directions for the development of the future generations of MMPIs.
31831256 The immunobiology of mTOR in autoimmunity. 2020 Jun The mechanistic target of rapamycin (mTOR) is a master regulator of the inflammatory response in immune and non-immune cells. In immune cells mTOR regulates metabolism to fuel cell fate decision, proliferation and effector functions. In non-immune cells, such as fibroblast, it controls inflammation-associated proliferation and migration/invasion, shapes the expression of cytokines and chemokines and promotes extracellular matrix remodeling and fibrosis. Hence, mTOR plays a critical role in chronic inflammation, where a continuous feedback between stromal cells and infiltrating immune cells result in tissue remodeling and organ damage. Activation of mTOR has been implicated in a number of chronic inflammatory diseases, especially rheumatic diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), sjögren syndrome (SS) and seronegative spondyloarthropathy (SpA). Here we review recent advances in our understanding of the mechanism of mTOR activation in inflammation, especially in rheumatic diseases. We further discuss recent findings regarding the beneficial and side effects of mTOR inhibition in rheumatic conditions.
31376421 Identification and structure-activity relationship (SAR) of chemical constituents from Dae 2019 Oct Osteoclastogenesis-related bone diseases including osteoporosis, rheumatoid arthritis, Paget's disease and periodontitis are worldwide occurred and cause severe health problems including bone fracture and bone cancer. However, A few studies have shown that Daemonorops draco (Willd.) Blume may decrease bone destruction and relieve bone cancer pain. In this research, we isolated and purified four known and two novel compounds from D. draco and investigated their anti-osteoclastogenesis activity using RAW264.7 cells. Among them, com.1 exhibited the most effective inhibitory activity on osteoclastogenesis with 78% inhibition at 10 μM and identified to be a novel natural flavan; and com.2 displayed a bit slighter inhibition (50% at 10 μM), indicating that the methylation of 7-hydroxyl group increased the anti-osteoclastogenesis activity. Moreover, nineteen commercial flavonoids were also performed in this study to investigate their inhibitory activity on osteoclastogenesis, and furtherly develop the SAR profile in flavonoid skeleton combined with the information of isolated compounds. Interestingly, the absence of substituents in B-ring and (3R)-hydroxyl group seems to play a crucial role in increasing anti-osteoclastogenesis activity.
31172335 The role of magnesium in different inflammatory diseases. 2019 Aug Magnesium deficiency (MgD) can cause inflammation in human body. The known mechanisms of inflammation caused by MgD include activation of phagocytic cells, opening of calcium channels, activation of the N-methyl-D-aspartate (NMDA) receptor, and activation of nuclear factor (NF)-κB. In addition, MgD causes systemic stress response through neuroendocrinological pathways. The inflammation caused by MgD can result in pro-atherogenic changes in the metabolism of lipoproteins, endothelial dysfunction, and high blood pressure. Studies suggest that magnesium may play an important role in the pathophysiology of some inflammatory diseases. Several clinical trials and laboratory studies have been done on the functional role of magnesium. In this study, we review some inflammatory diseases, in which the magnesium has a role in their pathophysiology. Among these diseases, diabetes, asthma, preeclampsia, atherosclerosis, heart damage, and rheumatoid arthritis have been highlighted.
31145122 Inflammatory joint diseases and atherosclerosis: time to look beyond the 'lipid paradox'. 2019 Aug PURPOSE OF REVIEW: Uncertainty persists about the contribution of lipids to the increased risk of cardiovascular disease (CVD) among rheumatoid arthritis and other inflammatory joint disease (IJD) patients. In reviewing recent research, we consider potential insights gained by quantifying lipoprotein particles directly, rather than by their lipid content. RECENT FINDINGS: Although inflammation often decreases LDL cholesterol (LDL-C), and anti-inflammatory medications often increase LDL-C, both inflammation and anti-inflammatory medications can increase atherogenic Apolipoprotein B (ApoB)-containing lipoprotein particles, attenuated by statins. CVD risk factors, that is, smoking, obesity, ApoB, may increase years prior to IJD diagnosis. Increased risks of nonatherosclerotic myocardial and pulmonary disease, heart failure and mortality may be directly related to disease activity, inflammation, and possibly to HDL particles and function. SUMMARY: For IJD patients, higher cumulative lifetime exposure to CVD risk factors accelerates atherosclerosis and subsequent CVD risk that is underestimated by current risk factor levels. CVD risk reduction in IJD requires aggressive and earlier reduction in CVD risk factors (ApoB lipoproteins, smoking, hypertension, diabetes, lack of physical activity), in addition to control of disease activity and inflammation. Lipid-lowering medications can attenuate anti-inflammatory medication-induced increases in ApoB and LDL-C, but can also reduce CVD risk due to cumulative lifetime exposure.
31085961 The Present and Future of Vagus Nerve Stimulation. 2019 May Epilepsy is one of the major chronic neurological diseases affecting many patients. Resection surgery is the most effective therapy for medically intractable epilepsy, but it is not feasible in all patients. Vagus nerve stimulation (VNS) is an adjunctive neuromodulation therapy that was approved in 1997 for the alleviation of seizures; however, efforts to control epilepsy by stimulating the vagus nerve have been studied for over 100 years. Although its exact mechanism is still under investigation, VNS is thought to affect various brain areas. Hence, VNS has a wide indication for various intractable epileptic syndromes and epilepsyrelated comorbidities. Moreover, recent studies have shown anti-inflammatory effects of VNS, and the indication is expanding beyond epilepsy to rheumatoid arthritis, chronic headaches, and depression. VNS yields a more than 50% reduction in seizures in approximately 60% of recipients, with an increase in reduction rates as the follow-up duration increases. The complication rate of VNS is 3-6%, and infection is the most important complication to consider. However, revision surgery was reported to be feasible and safe with appropriate measures. Recently, noninvasive VNS (nVNS) has been introduced, which can be performed transcutaneously without implantation surgery. Although more clinical trials are being conducted, nVNS can reduce the risk of infection and subsequent device failure. In conclusion, VNS has been demonstrated to be beneficial and effective in the treatment of epilepsy and various diseases, and more development is expected in the future.
31083446 Oceans as a Source of Immunotherapy. 2019 May 10 Marine flora is taxonomically diverse, biologically active, and chemically unique. It is an excellent resource, which offers great opportunities for the discovery of new biopharmaceuticals such as immunomodulators and drugs targeting cancerous, inflammatory, microbial, and fungal diseases. The ability of some marine molecules to mediate specific inhibitory activities has been demonstrated in a range of cellular processes, including apoptosis, angiogenesis, and cell migration and adhesion. Immunomodulators have been shown to have significant therapeutic effects on immune-mediated diseases, but the search for safe and effective immunotherapies for other diseases such as sinusitis, atopic dermatitis, rheumatoid arthritis, asthma and allergies is ongoing. This review focuses on the marine-originated bioactive molecules with immunomodulatory potential, with a particular focus on the molecular mechanisms of specific agents with respect to their targets. It also addresses the commercial utilization of these compounds for possible drug improvement using metabolic engineering and genomics.
31001379 Intra- and Inter-observer Variability in Different Methods of Measuring Carpal Collapse. 2019 Mar Introduction: Carpal collapse of wrist occurs in disorders like rheumatoid arthritis and Kienbock's disease. Three techniques have been described to measure carpal collapse. First, the carpal height ratio (CHR), measured by dividing carpal height by 3rd metacarpal length. Second, the revised carpal height ratio (RCH ratio), measured by dividing carpal height by length of capitate. Third, capitate radius distance (CR index), measured by shortest distance between distal edge of radius and the proximal edge of capitate. The index publications describe good reliability of all these but which method out of the three is best in terms of intra- and inter-observer variability is not known. The purpose of this study was to find out which method had the least inter- and intra-observer variability for determining carpal collapse. Materials and Methods: Fifty normal wrist postero-anterior radiographs were studied by three assessors who measured CHR, RCH ratio and CR index separately. The measurements were repeated after one month by all the three observers. The results were then statistically analysed. Results: The p-value was <0.001 in all the three assessors in CR index meaning that the intra-observer variability was least in CR index. For the inter-observer variability intra class coefficient of 0.9 indicated that the CR index has the least variability. Conclusion: CR index is the most reproducible method to measure carpal collapse. The method which provides accurate measurement of carpal collapse will allow better staging of carpal disorders.