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ID PMID Title PublicationDate abstract
33584521 Optic Perineuritis and Its Association With Autoimmune Diseases. 2020 Background: Optic perineuritis (OPN) is a special optic neuropathy that has a distinct etiology from neuromyelitis optica spectrum disorders (NMOSDs) or multiple sclerosis (MS)-related optic neuritis (ON). The mechanisms of how this inflammation developed and invaded the nerve sheath remain unknown. This study is aimed to analyze the etiology and different clinical characteristics of OPN in a Chinese patient population. Methods: Neuro-ophthalmological examination, orbit magnetic resonance imaging (MRI) and a series of blood samples were used in this retrospective observational cohort study to compare characteristics of OPN with idiopathic demyelination optic neuritis (IDON). Results: Forty-four OPN cases (74 eyes) and 61 IDON cases (78 eyes) were analyzed. OPN cases included 33 cases (59 eyes) were associated with specific autoimmune diseases, 10 cases (13 eyes) were associated with infection diseases, 1 case was idiopathic disease. The causes of OPN with CTD were Graves' disease, Immunoglobulin G4-related disease (IgG-4 RD), granulomatosis with polyangiitis (GAP), systemic lupus erythematosus (SLE), Sarcoidosis, Rheumatoid arthritis, scleroderma, Behcet's disease, and gout. All patients received orbital MRI. Overall, 33 cases showed orbit fat infiltration. Specifically, nine cases with IgG-4 RD showed trigeminal nerve branch involvement, 12 cases with Graves' disease showed extraocular muscle belly enlargement, and 4 cases with GAP showed pterygopalatine fossa pseudotumor. Compared to IDON patients, OPN patients were older (p = 0.004) and more likely bilateral involvement 26 (78.79%) patients had bilateral involvement in OPN group vs. 17 (27.87%) in the IDON group (p < 0.001). Visual acuity scores using LogMAR testing was better in OPN patients compared to those with IDON, 0.55 ± 0.91 vs. 1.19 ± 1.24 (p < 0.001). Other ophthalmologic findings unique to the OPN group include 11 (33.33%) cases of ptosis, nine (27.27%) cases of diplopia, and 10 (30.30%) cases of exophthalmos, compared to zero cases of these conditions in the IDON group. Eight (13.11%) IDON patients also had multiple sclerosis (MS) and 7 (11.48%) patients had neuromyelitis which was significantly more than the zero patients in OPN group (p = 0.04). Conclusions: OPN had distinct etiologies and clinical characteristics from IDON and is more often associated with autoimmune diseases. Using OPN characteristics to diagnose autoimmune diseases should prove useful for clinicians when presented with patients that have multiorgan dysfunction that include ophthalmologic findings.
33418884 GABA(B)-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice. 2021 Jan 6 Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABA(A)-Rs and/or GABA(B)-Rs). Treatment with GABA, which activates both GABA(A)-Rs and GABA(B)-Rs), and/or a GABA(A)-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABA(B)-Rs. Here, we tested lesogaberan, a peripherally restricted GABA(B)-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin(+) cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABA(B)-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABA(B)-Rs and GABA(A)-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.
33352479 When symptoms become side effects: Development of the side effect attribution scale (SEAS) 2021 Feb OBJECTIVES: Symptom misattribution is a central process in the nocebo effect but it is not accurately assessed in current side effect measures. We have developed a new measure, the Side Effect Attribution Scale (SEAS), which examines the degree to which people believe their symptoms are treatment side effects. METHODS: The SEAS was tested in three New Zealand studies: a vaccination sample (n = 225), patients with gout or rheumatoid arthritis (n = 102), and patients switching to a generic medicine (n = 69). The internal reliability of the scale was examined using Cronbach's alpha. To assess validity, the Side Effect Attribution Total Score and Side Effect Attribution Binary Score were related to a number of psychological measures associated with side effect reporting. RESULTS: The scale showed good internal reliability across the three studies, with Cronbach alphas ranging from 0.840 to 0.943. Analysis of the effect sizes showed that the Attribution Total Score was generally more strongly associated with nocebo responding than Attribution Binary Score. Participants had greater Side Effect Attribution Total Scores if they had higher expectations for vaccination side effects (r = 0.18, p = .028), more worry about future vaccine effects (r = 0.16, p = .046), a higher perceived sensitivity to medicines (r = 0.50, p < .001), greater anxiety (r = 0.25, p = .016), greater intentional non-adherence (r = 0.30, p = .003), greater medicine information seeking (r = 0.26, p = .010), lower trust in pharmaceutical agencies (r = -0.29, p = .026), and lower medicine efficacy beliefs (r = -0.46, p < .001). CONCLUSIONS: The SEAS provides a more nuanced assessment of symptom attribution beliefs. It appears to be more sensitive measure than just a side effect total, as it is associated with a greater number of relevant psychological variables. Future research should examine the scale in other populations and settings.
33276950 In vitro display evolution of the PURE system-expressed TNFα-binding unnatural cyclic pe 2021 Jan 1 Tumor necrosis factor-alpha (TNFα) is a multifunctional cytokine associated with inflammation, immune responses, and autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. In the present study, we performed in vitro selection, systematic evolution of ligands by exponential enrichment (SELEX) against human TNFα from mRNA-displayed peptide library prepared with Escherichia coli-reconstituted cell-free transcription/translation system (PURE system) and cyclized by N-chloroacetyl-N-methyl-d-phenylalanine incorporated by genetic code expansion (sense suppression). We identified a novel TNFα-binding thioether-cyclized peptide that contains an N-methyl-d-phenylalanine. Since cyclic structure and presence of an N-methyl-d-amino acid can increase proteolytic stability, the TNFα binding peptide has potential to be used for therapeutic, research and diagnostic applications.
33174109 Incidence of COVID-19 in patients with rheumatic disease: is prior health education more i 2021 Apr The COVID-19 pandemic has led to major changes in clinical practice on a global scale in order to protect patients. This includes the identification of vulnerable patients who should "shield" in order to reduce the likelihood of contracting SARS-CoV2. We used national specialty guidance and an adapted screening tool to risk stratify patients identified from our prescribing and monitoring databases, and identify those needing to shield (score ≥ 3) using information from departmental letters, online general practice records and recent laboratory investigations. We collated underlying rheumatological conditions and risk factors. Two months into the shielding process, we examined the COVID-19 status of these patients using hospital laboratory records and compared to population level data. Of 887 patients assessed, 248 (28%) scored ≥ 3 and were sent a standard shielding letter. The most common risk factor in the shielding letter group was age ≥ 70 years and/or presence of a listed co-morbidity (199 patients). The most common rheumatology conditions were rheumatoid arthritis (69.4%), polymyalgia rheumatica (8.5%) and giant cell arteritis (8.5%). Coronavirus incidence rates were similar in the shielding letter group (0.403%) and in the UK population (0.397%). However, we found a trend towards lower incidence (0.113%) in our whole cohort (RR 0.28, 95%CI 0.04-2.01 for the whole cohort compared to UK population). The trend towards lower incidence in this cohort could be because of prior education regarding general infection risk and response to public health messages. While risk stratification and shielding could be effective, prior education regarding general infection risk and public health messages to enhance health protection behaviours during a pandemic may have equal or more important roles. Key Points • Patients on treatment for rheumatic disorders showed a trend for lower incidence of COVID-19 transmission irrespective of shielding letter status • This could potentially be because of prior education regarding infection risk received when starting on disease-modifying medication • Health education influencing health protection behaviours may be of equal or more importance than shielding information in reducing transmission of SARS-CoV-2.
33074948 Epidemiology of Autoimmune Hepatitis (AIH) in the United States Between 2014 and 2019: A P 2021 Nov BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a chronic, inflammatory disease of the liver with increasing prevalence. However, limited epidemiological data exist for the prevalence of AIH in the United States. We used a large database to describe the prevalence of AIH in the United States and the autoimmune diseases associated with it. APPROACH AND RESULTS: Data was collected from a commercial database (Explorys Inc., Cleveland, OH), an aggregate of Electronic Health Record data from 26 major integrated health care systems in the United States. We identified a cohort of patients with a diagnosis of AIH from April 2014 to April 2019 based on a Systemized Nomenclature of Medicine-Clinical Terms and calculated the prevalence of AIH. Of the 37,161,280 individuals active in the database from April 2014 to 2019, we identified 11,600 individuals with a diagnosis of AIH with an overall prevalence rate of 31.2/100,000. The prevalence of AIH was increased in females compared with males [odds ratio (OR)=3.21, P<0.0001], elderly (aged above 65 y) compared with adults (aged 18 to 65 y) and children (aged below 18 y) (OR=2.51, P<0.0001) and whites compared with African Americans, Asians, and Hispanics (OR=1.12, P<0.0001). Moreover, patients with AIH were more likely to have Sjögren syndrome, systemic lupus erythematosus, ulcerative colitis, celiac disease, rheumatoid arthritis, Crohn's disease, and autoimmune thyroiditis as compared with patients without AIH. CONCLUSIONS: We found that the estimated prevalence of AIH in the United States is 31.2/100,000, which is comparable to the reported prevalence of AIH in Europe. We confirmed that AIH has a strong association with other autoimmune diseases studied in the literature.
32959462 Relationship between natural and infection-induced antibodies in systemic autoimmune disea 2021 Jan Infection or vaccine-induced T cell-dependent immune response and the subsequent high-affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease-specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine-induced and disease-related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme-linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti-CS) and F4 fragment (anti-F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti-measles IgG and anti-dsDNA IgG/IgM autoantibodies were measured using commercial and in-house indirect ELISA tests. In all SAD groups the anti-measles IgG-seropositive cases showed significantly higher anti-CS IgG titers (P = 0·011). In anti-dsDNA IgG-positive SLE patients, we detected significantly higher levels of anti-CS and anti-F4 IgG nAAbs (P = 0·001 and < 0·001, respectively). Additionally, we found increased levels of IgM isotypes of anti-CS and anti-F4 nAAbs in anti-dsDNA IgM-positive SLE patients (P = 0·002 and 0·016, respectively). The association between IgG isotypes of pathogen- or autoimmune disease-related antibodies and the IgG nAAbs may underscore the immune response-inducible nature of the diseases investigated. The relationship between protective anti-dsDNA IgM and the IgM isotype of anti-F4 and anti-CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.
32929180 An objective method of diagnosing hydroxychloroquine maculopathy. 2021 Jul BACKGROUND: Hydroxychloroquine (HCQ) maculopathy is irreversible; primary prevention is done by regular monitoring. Guidelines of the Royal College of Ophthalmologists identify definite toxicity as having abnormal results of two screening tests, we present a quantitative method for interpreting these guidelines. METHODS: We obtained ocular coherence tomography (OCT) scans of 100 patients who have been on HCQ for 5 years or more (patients) and 70 age-matched controls. Both groups had 10'2 visual field (VF) test. We used linear regression to determine the cut-off points for each of the eight Early Treatment of Diabetic Retinopathy Study (ETDRS) macular sectors for the VF and OCT. We calculated the probability of developing maculopathy using logistic regression. RESULTS: Mean patient age: 59.9 years, 85% females, no statistically significant age difference between the patients and the control groups. DIAGNOSIS: 64% rheumatoid arthritis, 14% Sjogren's syndrome, 16% systemic lupus and 6% various other rheumatology conditions. Mean duration of use was 6.3 years. Logistic regression results show strong negative correlation between the outer nuclear layer (ONL) volume and probability of toxicity. Goodness of fit was tested using Hosmer and Lemeshow test that indicates a high significance with a high P-value of 1. CONCLUSIONS: Combining the ONL volume reduction and VF retinal sensitivity reduction per each of the eight ETDRS macular sectors provides an accurate and objective way of diagnosing HCQ maculopathy, this helps busy eye units establishing an optometrist-led or virtual service because it is independent of the assessor's level of experience.
32881084 Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-re 2021 Feb Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively. There is a potential to develop novel small molecule IL-6 antagonists derived from understanding the structural basis for IL-6/IL-6Rα interactions. Here, we combine homology modeling with extensive molecular dynamics (MD) simulations to examine the association of hIL-6 with IL-6Rα. A comparison with MD of apo hIL-6 reveals that the binding of hIL-6 to IL-6Rα induces structural and dynamic rearrangements in the AB loop region of hIL-6, disrupting intraprotein contacts and increasing the flexibility of residues 48 to 58 of the AB loop. In contrast, due to the involvement of residues 59 to 78 in forming contacts with the receptor, these residues of the AB loop are observed to rigidify in the presence of the receptor. The binary complex is primarily stabilized by two pairs of salt bridges, Arg181 (hIL-6)- Glu182 (IL-6Rα) and Arg184 (hIL-6)- Glu183 (IL-6Rα) as well as hydrophobic and aromatic stacking interactions mediated essentially by Phe residues in both proteins. An interplay of electrostatic, hydrophobic, hydrogen bonding, and aromatic stacking interactions facilitates the formation of the hIL-6/IL-6Rα complex.
34727118 Distribution of bony erosions in feet and performance of two bone erosion scores: A dual-e 2021 OBJECTIVES: To assess the distribution of bone erosions and two erosion scores in the feet of patients with gout and analyze the association between erosion scores and monosodium urate (MSU) crystal deposition using dual-energy computed tomography (DECT). MATERIALS AND METHODS: We included all patients who underwent DECT of both feet between 2016 and 2019 in our radiology department, with positive detection of MSU deposits. Data on sex, age, treatment, serum urate, and DECT urate volumes were obtained. CT images were analyzed to score bone erosions in 31 sites per foot by using the semi-quantitative method based on the Rheumatoid Arthritis MRI Scoring (RAMRIS) system and the Dalbeth-simplified score. Reproducibility for the two scores was calculated with intraclass correlation coefficients (ICCs). Correlations between clinical features, erosion scores and urate crystal volume were analyzed by the Spearman correlation coefficient (r). RESULTS: We studied 61 patients (mean age 62.0 years); 3,751 bones were scored. The first metatarsophalangeal joint and the midfoot were the most involved in terms of frequency and severity of bone erosions. The distribution of bone erosions was not asymmetrical. The intra- and inter-observer reproducibility was similar for the RAMRIS and Dalbeth-simplified scores (ICC 0.93 vs 0.94 and 0.96 vs 0.90). DECT urate volume was significantly correlated with each of the two erosion scores (r = 0.58-0.63, p < 0.001). There was a high correlation between the two scores (r = 0.96, p < 0.001). CONCLUSIONS: DECT demonstrates that foot erosions are not asymmetric in distribution and predominate at the first ray and midfoot. The two erosion scores are significantly correlated with DECT urate volume. An almost perfect correlation between the RAMRIS and Dalbeth-simplified scores is observed.
34642059 Temporal Relationship of Corticosteroid Injection and Open Release for Trigger Finger and 2021 Oct 9 PURPOSE: Previous single-institution studies have shown a relationship between corticosteroid injection and infection after surgery if open trigger release occurs within 90 days. We queried an insurance claims database to evaluate the temporal relationship between a corticosteroid injection and the development of a surgical site infection requiring secondary surgery in patients undergoing trigger release. METHODS: The PearlDiver database was queried for adults who underwent unilateral trigger finger release surgery from 2012 to 2018. The total number of injections, time from last injection to surgery, and preoperative antibiotic use were determined, in addition to the rates of postoperative administration of antibiotics and deep infection requiring surgery at 30, 60, and 90 days after surgery. Logistic regression analysis was used to evaluate the odds of deep infection at 30, 60, and 90 days. RESULTS: A total of 14,686 patients were included; at least 1 corticosteroid injection was administered to 5,173 patients prior to surgery. When grouped based on whether a corticosteroid injection was administered prior to surgery, the postoperative infection rates between the groups were similar at 30, 60, and 90 days. When surgery was performed within 1 month of injection, increased odds of deep infection requiring irrigation and debridement were seen at 60 (odds ratio 2.92 [1.01-7.52]) and 90 days (odds ratio 3.01 [1.13-7.25]). Postoperative antibiotic use in the groups with and without a preoperative injection was similar at all queried time points, but patients who underwent open trigger finger release within 1 month of a prior injection had significantly increased odds (odds ratio 5.77 [1.41-22.06]) of using antibiotics after surgery. Male sex, a higher Elixhauser comorbidity index, and rheumatoid arthritis were additional independent risk factors for a deep infection. CONCLUSIONS: Patients who undergo open trigger release within 1 month of a corticosteroid injection are at increased odds of developing a postoperative infection requiring surgical debridement. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.
33986741 Regulation of Inflammatory Response by Transmembrane Adaptor Protein LST1. 2021 LST1 is a small adaptor protein expressed in leukocytes of myeloid lineage. Due to the binding to protein tyrosine phosphatases SHP1 and SHP2 it was thought to have negative regulatory function in leukocyte signaling. It was also shown to be involved in cytoskeleton regulation and generation of tunneling nanotubes. LST1 gene is located in MHCIII locus close to many immunologically relevant genes. In addition, its expression increases under inflammatory conditions such as viral infection, rheumatoid arthritis and inflammatory bowel disease and its deficiency was shown to result in slightly increased sensitivity to influenza infection in mice. However, little else is known about its role in the immune system homeostasis and immune response. Here we show that similar to humans, LST1 is expressed in mice in the cells of the myeloid lineage. In vivo, its deficiency results in alterations in multiple leukocyte subset abundance in steady state and under inflammatory conditions. Moreover, LST1-deficient mice show significant level of resistance to dextran sodium sulphate (DSS) induced acute colitis, a model of inflammatory bowel disease. These data demonstrate that LST1 regulates leukocyte abundance in lymphoid organs and inflammatory response in the gut.
33831690 Pterocephin A, a novel Triterpenoid Saponin from Pterocephalus hookeri induced liver injur 2021 May BACKGROUND: Pterocephalus hookeri (C. B. Clarke) Höeck, a Tibetan medicine widely used for treatment of rheumatoid arthritis, was recorded in Chinese Pharmacopoeia (2020 version) with slight toxicity. The liver injury was observed in mice with administration of n-butanol extract (BUE) in our previously study. However, the toxic components and the mechanism were still unrevealed. PURPOSE: The present study was aimed to isolate and structural elucidate of the toxic compound pterocephin A (PA), as well as evaluate its liver toxicity and investigate its mechanism. METHODS: PA was isolated from the BUE of P. hookeri. Its structure was determined by analysis of HRMS, NMR and ECD data. L-02 cellular viability, LDH, ALT, AST, ROS, intracellular Ca(2+) and the fluidity of cell membrane were assessed by multifunctional microplate reader. The PI staining, cell membrane permeability assessment, and mitochondrial fluorescence staining analysis were determined through the fluorescence microscope. Liver samples for mice were assessed by pathological and immunohistochemistry analysis. Expression levels of indicated proteins were measured by western blotting assays. RESULTS: PA was determined as a previously undescribed oleanolane-type triterpenoid saponin. In vitro study revealed PA significantly induced hepatotoxicity by inhibition of L-02 cell growth, abnormally elevation of ALT and AST. Mechanically, PA induced the damage of cell membrane, fragmentation of mitochondria, and subsequently increase of intracellular Ca(2+) and ROS levels, which trigged by necroptosis with the activation of RIP1 and NF-κB signaling pathways. In vivo study confirmed PA could induce liver injury in mice with observation of the body weight loss, increasing of serum ALT and AST, and the histopathological changes in liver tissues. CONCLUSION: Our present study indicated that PA was an undescribed toxic constituent in P. hookeri to induce liver injury in mice by activation of necroptosis and inflammation. And the findings are of great significance for the clinical use safely of this herb.
33821440 Unsaturated fatty acids as a co-therapeutic agents in cancer treatment. 2021 Mar Chemotherapy is standard treatments for many malignancies. However, in most cases, this method is not able to induce apoptosis and in many cases, with cancer recurrence, leads to patient death. There are several procedure to control and suppress malignant cells, but among these methods, administration of É·-3 fatty acids and É·-6 fatty due to their destructive effects on cancer cells is more prominent. Many clinical studies have shown beneficial effects of É·-3 and É·-6 fatty acids in cardiovascular disorders, asthma, rheumatoid arthritis, osteoporosis and in most cancers such as colon, breast, prostate and other malignancies. Studies showed that polyunsaturated fatty acids (PUFAs) have a toxic effect on cancer cells. However, the exact mechanism of how É·- fatty acids affect cancer cells is still unknown. In this review alternative issues of malignancies co-treatments agents such as PUFAs have been studied. Also, the latest known PUFAs mechanisms on malignancies have been described.
33677998 Classification of Distinct Endotypes in Human Skin Scarring: S.C.A.R.-A Novel Perspective 2022 Mar Significance: Skin scarring is a permanent, irreversible end point of cutaneous injury. However, not everyone will acquire the same exact scar type. Skin scarring is generally recognized as complex with significant variability in individuals' scar type and response to treatment. Despite these tangible differences in treatment response, to date there has been no simplified approach in defining spectrum of skin scarring in relation to prediction and outcome post-treatment. Thus, in this study we propose that skin scarring consists of distinct endotypes, which is characterized by their specific pathology. Four distinct scar endotypes can be observed: (1) Stretched (flat), (2) Contracted, (3) Atrophic (depressed), and (4) Raised scarring, which can be abbreviated to S.C.A.R. endotypes. Each of these endotypes can certainly include subphenotypes and each phenotype can be present in more than one endotype. To define these endotypes, we also present a structured approach in assessment of all relevant parameters in skin scar evaluation including clinical (scar symptoms and signs) and nonclinical parameters (device measurements of structural, mechanical, and physiological properties of scars as well as gene and protein laboratory studies). Recent Advances: Scars can be phenotypically characterized based on a multitude of parameters assessed; however, not all scar types will share all the same characteristics. This leads to the question of whether skin scarring is a single disease entity with varying phenotypic characteristics or should be classed as several disease entities that have certain similar parameters. We suggest the latter and propose distinct scarring phenotypes arise mainly owing to genetic and environmental susceptibilities associated with the development of each specific scar endotype. Characteristic features of skin scarring, however, can be objectively and quantitively evaluated and used as an aid in the theranostic goal-directed management of scarring. Critical Issues: The concept of identifying different endotypes is key in formulating personalized treatments with improved outcomes beyond what is achieved with current nonspecific approaches in scar management. This approach has gained interest and significant traction in several other medical conditions including asthma, rheumatoid arthritis, and atopic dermatitis. Future Directions: To begin identifying distinct endotypic features in skin scarring, it is important to have a better understanding of underlying pathological mechanisms leading to further insight into the heterogeneous nature of skin scarring endotypes. This approach may lead to improved theranostic outcomes and further understanding of the pathophysiology of the complex nature of human skin scarring.
33649426 Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and ca 2021 Mar 1 Methylation of alkyl thiols is a biotransformation pathway designed to reduce thiol reactivity and potential toxicity, yet the gene and protein responsible for human alkyl thiol methyltransferase (TMT) activity remain unknown. Here we demonstrate with a range of experimental approaches using cell lines, in vitro systems, and recombinantly expressed enzyme, that human methyltransferase-like protein 7B (METTL7B) catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to hydrogen sulfide (H(2)S) and other exogenous thiol small molecules. METTL7B gene modulation experiments, including knockdown in HepG2 cells and overexpression in HeLa cells, directly alter the methylation of the drug captopril, a historic probe substrate for TMT activity. Furthermore, recombinantly expressed and purified wild-type METTL7B methylates several thiol compounds, including H(2)S, 7α-thiospironolactone, L-penicillamine, and captopril, in a time- and concentration-dependent manner. Typical for AdoMet-dependent small molecule methyltransferases, S-adenosyl-L-homocysteine (AdoHcy) inhibited METTL7B activity in a competitive fashion. Similarly, mutating a conserved aspartate residue, proposed to anchor AdoMet into the active site, to an alanine (D98A) abolished methylation activity. Endogenous thiols such as glutathione and cysteine, or classic substrates for other known small molecule S-, N-, and O-methyltransferases, were not substrates for METTL7B. Our results confirm, for the first time, that METTL7B, a gene implicated in multiple disease states including rheumatoid arthritis and breast cancer, encodes a protein that methylates small molecule alkyl thiols. Identifying the catalytic function of METTL7B will enable future pharmacological research in disease pathophysiology where altered METTL7B expression and, potentially H(2)S levels, can disrupt cell growth and redox state.
33567628 Nutraceuticals against Oxidative Stress in Autoimmune Disorders. 2021 Feb 8 Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.
33560443 Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Sy 2021 Dec 11 OBJECTIVE: To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain. METHODS: A systematic search was carried out until April 2020 for clinical studies of N-acetylcysteine in the management of any persistent or recurrent chronic pain condition for adults ≥ 18 years old. Risk of bias was assessed using the validated risk of bias tools. When appropriate, a meta-analysis using a random-effects model was performed, with a fixed-effect model for sensitivity analysis. RESULTS: Nine studies (n = 863) were included (five randomized controlled trials [RCTs], two open-label non-comparative studies and two comparative studies), that evaluated patients with sickle cell disease (3), complex regional pain syndrome (1), pelvic pain/endometriosis (2), rheumatoid arthritis (1), diabetic neuropathy (1), and chronic neuropathic pain (1). In the pooled analysis of three RCTs, N-acetylcysteine did not reduce pain intensities (SMD -0.21, 95% confidence interval [CI]: -0.33 to 0.75, random-effects), improve functional outcomes (SMD 0.21, 95% CI -0.33 to 0.75) or quality of life (SMD 0.60, 95% CI: -4.44 to 5.64); however, sensitivity analysis with a fixed effect model demonstrated an effect for pain intensities and function. Due to adverse events being inconsistently reported, no conclusion could be made regarding safety of N-acetylcysteine in chronic pain. CONCLUSIONS: While there is some evidence to indicate N-acetylcysteine may provide analgesic efficacy for certain pain conditions, there is insufficient evidence to provide definitive evidence on NAC in chronic pain management. Larger-size RCTs spanning a variety of chronic pain conditions are needed to determine N-acetylcysteine's role, if any, in pain medicine.
33241941 Mindfulness-Based Cognitive Therapy for Treating Chronic Pain A Systematic Review and Meta 2021 Mar Chronic pain is a significant public health problem with emotional and disabling factors, which may not completely respond to current medical treatments such as opioids. The systematic review and meta-analysis aimed to examine the effectiveness and safety of MBCT for patients with chronic pain. Database searches of PubMed, Medline, EMBASE, the Cochrane Library, PsycINFO, Web of Science, Scopus and CINAHL up to 15 October 2019. Included studies assessed with the Cochrane risk-of-bias tool. Eight RCTs involved 433 patients, including chronic low back pain, fibromyalgia, migraine, rheumatoid arthritis and mix etiology. MBCT intervention demonstrated a short-term improvement on depression mood [standardized mean difference -0.72; 95% confidence interval = -1.22 to -0.22, p = 0.005] compared with usual care and was associated with short-term improvement in mindfulness compared with non-MBCT [SMD 0.51; 95% CI = 0.01 to 1.01, p = 0.04]. Between-group differences in pain intensity, pain inference and pain acceptance were not significant at short- or long-term follow-up. Compared to active treatments, MBCT intervention not found significant differences in either short- or long-term outcomes. MBCT showed short-term efficacious on depressed mood and mindfulness of chronic pain patients. Longer follow-ups, large sample and rigorous RCTs that can be best understand remaining uncertainties needed.
35116080 Switching from originator adalimumab to biosimilar SB5 in a rheumatology cohort: persisten 2021 AIMS: Medical and non-medical switching strategies have been adopted in Europe in the last few years. We aimed to investigate persistence on treatment with a SB5 Adalimumab (SB5) biosimilar after switching from Adalimumab (ADA) originator among patients with inflammatory rheumatic musculoskeletal diseases (iRMD), identifying possible predictors of drug interruption and describing adverse events. METHOD: iRMD patients previously switched to SB5 after at least 6 months of ADA were enrolled. Data on concomitant medications, disease flares, and persistence on SB5 up to the last available follow up were collected retrospectively. Kaplan-Meier and Cox regression models were used. RESULT: A total of 172 patients (106 females, ADA duration 5.8 ± 3.8 years) were enrolled, including 34 rheumatoid arthritis, 59 psoriatic arthritis, and 61 axial spondyloarthritis patients. In a 10 ± 3 months follow up, 65 (37.8%) patients presented with adverse events, with 46 (26.7%) showing a clinically defined disease flare (no disease activity and patient reported outcomes assessment were available); 24 patients interrupted SB5 permanently (among them, 11 back-switched to ADA and 8 were prescribed a different biological therapy). Probability of persistence on SB5 was 94.7% at 6 months and 85.1% at 12 months. Baseline corticosteroid [hazard ratio (HR) 3.209, 95% confidence interval (CI) 1.193-8.635, p = 0.021] and therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) (HR 2.876, 95% CI 1.229-6.727, p = 0.015), as well as the baseline corticosteroid dose (HR 1.200, 95%CI 1.026-1.403, p = 0.022) were predictors of drug interruption. CONCLUSION: Our data on persistence of treatment and adverse events are in line with previous reports. Further large cohort studies may confirm baseline corticosteroid and NSAIDs use as predictors of SB5 interruption, helping to identify patients at higher risk of failure after switching.