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ID PMID Title PublicationDate abstract
30518476 Predicting Costs Exceeding Bundled Payment Targets for Total Joint Arthroplasty. 2019 Mar BACKGROUND: The Center for Medicare and Medicaid Services has instituted bundled reimbursement models for total joint arthroplasty (TJA), which includes target prices for each procedure. Some patients exceed these targets; however, currently there are no tools to accurately predict this preoperatively. We hypothesized that a validated comorbidity index combined with patient demographics would adequately predict excess cost-of-care prior to hospitalization. METHODS: Two thousand eighty-four primary unilateral TJAs performed at a single tertiary center were retrospectively examined. Data were extracted from medical records and a predictive model was built from 30 comorbidities and 7 patient demographic factors (age, gender, race, body mass index, American Society of Anesthesiologists score, smoking status, and marital status). Following parameter selection, a final multivariable model was created, with a corresponding nomogram for interactive visualization of probability for excess cost. RESULTS: Six hundred twelve patients (29%) had cost-of-care exceeding the target price. The final model demonstrated adequate predictive discrimination for cost-of-care exceeding the target price (area under the receiver operator characteristic curve: 0.747). Factors associated with excess cost included age, gender, marital status, American Society of Anesthesiologists score, body mass index, and race, as well as 7 Elixhauser comorbidities (alcohol use, rheumatoid arthritis, diabetes, electrolyte disorders, neurodegenerative disorders, psychoses, and pulmonary circulatory disorders). CONCLUSION: A novel patient model composed of a subset of validated comorbidities and demographic variables provides adequate discrimination in predicting excess cost within bundled payment models for TJA. This not only helps identify patients who would benefit from preoperative optimization, but also provides evidence for modification of future bundled reimbursement models to adjust for nonmodifiable risk factors.
30507027 Frequency of mental disorders among chronic pain patients with or without fibromyalgia in 2018 Dec AIM: To explore the characteristics of psychiatric morbidity in chronic pain patients who present with or without fibromyalgia. METHODS: Patients are referred to our chronic pain clinic from primary medical institutions, as we are a secondary medical institution. Although some patients have chronic pain, they have no clear organic disorder such as rheumatoid arthritis to account for the pain. Among the 367 new patients seen during the period from March 2009 to August 2012, 347 patients underwent psychiatric evaluation in face-to-face interviews with mental health specialists before a physical examination. RESULTS: Of the 347 patients examined, at least one psychiatric diagnosis was made for 94.6%. The average number of DSM-IV-TR diagnoses was 1.46 in the 330 chronic pain patients who had at least one psychiatric diagnosis. The breakdown of the number of psychodiagnoses was one in 60.8%, two in 27.1%, three in 4.9%, and more than three in 2.3% chronic pain patients with or without fibromyalgia. In fibromyalgia patients, the highest relative frequencies were found for somatoform disorders (76%), followed by dysthymic disorder (17%) and major depressive disorder (15%). In patients without fibromyalgia, the highest relative frequencies were found for somatoform disorders (64%), followed by major depressive disorder (15%) and dysthymic disorder (14%). Psychiatric disorders were found in 96.9% of fibromyalgia patients, and in 93.5% of chronic pain patients without fibromyalgia in Japan (no significant difference using chi-square test). CONCLUSION: Results show that chronic pain patients with or without fibromyalgia are extremely likely to be diagnosed with a psychiatric disorder.
30400332 Vitamin D: Nutrient, Hormone, and Immunomodulator. 2018 Nov 3 The classical functions of vitamin D are to regulate calcium-phosphorus homeostasis and control bone metabolism. However, vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and deregulation of the immune system, such as diabetes, asthma, and rheumatoid arthritis. These observations, together with experimental studies, suggest a critical role for vitamin D in the modulation of immune function. This leads to the hypothesis of a disease-specific alteration of vitamin D metabolism and reinforces the role of vitamin D in maintaining a healthy immune system. Two key observations validate this important non-classical action of vitamin D: first, vitamin D receptor (VDR) is expressed by the majority of immune cells, including B and T lymphocytes, monocytes, macrophages, and dendritic cells; second, there is an active vitamin D metabolism by immune cells that is able to locally convert 25(OH)D₃ into 1,25(OH)₂D₃, its active form. Vitamin D and VDR signaling together have a suppressive role on autoimmunity and an anti-inflammatory effect, promoting dendritic cell and regulatory T-cell differentiation and reducing T helper Th 17 cell response and inflammatory cytokines secretion. This review summarizes experimental data and clinical observations on the potential immunomodulating properties of vitamin D.
30385794 Planarians as models to investigate the bioactivity of gold(I) complexes in vivo. 2018 Nov 1 Gold(I)-containing complexes are used in drug discovery research for rheumatoid arthritis, cancer, and parasitic infections. In this study, we tested the bioactivity of gold(I) complexes in vivo using planarians. The planarian Schmidtea mediterranea possesses orthologues of tumor suppressor genes, such as p53, that, when silenced, cause deregulation of cell proliferation and apoptosis. In this context, we tested two triethylphosphine-gold(I) complexes (AdO and AdT) to determine if they can attenuate phenotypes that result from p53 inhibition. First, we identified the drug concentration that did not affect survival or regeneration and evaluated the drug's effect on cell division and apoptosis. We found that AdT treatment decreased the number of mitotic cells and that all drug treatments increased the number of apoptotic cells. We then performed p53(RNAi) and drug treatments concomitantly and observed the phenotype progression. Drug treatment increased survival three-fold and decreased apoptosis, which resulted in an attenuated phenotype. Our results indicate that planarians can be treated with gold(I) complexes, and that this treatment can diminish the p53(RNAi) phenotype and extend survival. In this work we show that planarians can be used as a model to study the in vivo effect of gold(I) complexes and to further investigate their mechanisms of action.
30216110 Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and a 2019 Feb Many bone diseases, such as osteoporosis and rheumatoid arthritis, are attributed to an increase in osteoclast number or activity; therefore, control of osteoclasts has significant clinical implications. This study shows how skullcapflavone II (SFII), a flavonoid with anti-inflammatory activity, regulates osteoclast differentiation, survival, and function. SFII inhibited osteoclastogenesis with decreased activation of MAPKs, Src, and cAMP response element-binding protein (CREB), which have been known to be redox sensitive. SFII decreased reactive oxygen species by scavenging them or activating nuclear factor-erythroid 2-related factor 2 (Nrf2), and its effects were partially reversed by hydrogen peroxide cotreatment or Nrf2 deficiency. In addition, SFII attenuated survival, migration, and bone resorption, with a decrease in the expression of integrin β(3), Src, and p130 Crk-associated substrate, and the activation of RhoA and Rac1 in differentiated osteoclasts. Furthermore, SFII inhibited osteoclast formation and bone loss in an inflammation- or ovariectomy-induced osteolytic mouse model. These findings suggest that SFII inhibits osteoclastogenesis through redox regulation of MAPKs, Src, and CREB and attenuates the survival and resorption function by modulating the integrin pathway in osteoclasts. SFII has therapeutic potential in the treatment and prevention of bone diseases caused by excessive osteoclast activity.-Lee, J., Son, H. S., Lee, H. I., Lee, G.-R., Jo, Y.-J., Hong, S.-E., Kim, N., Kwon, M., Kim, N. Y., Kim, H. J., Lee, Y. J., Seo, E. K., Jeong, W. Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling.
30185360 Serum sCTLA-4 levels and clinical manifestations in ankylosing spondylitis patients. 2018 Jul OBJECTIVE: T cell abnormal activation is thought to have a main role in the etiology of ankylosing spondylitis (AS). While cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is suppressing the immune system, in previous studies serum soluble CTLA-4 (sCTLA-4) was detected at high amounts in autoimmune disorders. We sought to evaluate the association between soluble CTLA-4 in serum and disease activity in AS patients. METHODS: Thirty-eight patients with AS, 28 rheumatoid arthritis (RA) patients, and 27 disease-free controls were enrolled to the study. The levels of sCTLA-4 were determined for each participant using an enzyme-linked immunosorbent assay. The erythrocyte sedimentation rate (ESR), C-reactive peptide, and demographic characteristics were documented. The data were analyzed by using relevant statistical methods. RESULTS: In comparison with RA patients and controls, patients with AS showed high sCTLA-4 levels (p<0.001). The sCTLA-4 levels did not correlate with the severity of the disease in AS patients (p=0.370). The ESR levels and Bath Ankylosing Spondylitis Disease Activity Index were correlated in AS patients (p=0.012). CONCLUSION: We evaluated the association between the disease severity of AS and sCTLA-4. Although, the correlation was not shown, sCTLA-4 was highest in the AS group. Further studies with larger samples should be completed to attain a better understanding of the AS etiology.
30106258 Association between rs2275913 single-nucleotide polymorphism of the interleukin-17A gene a 2018 Jun AIM: Interleukin-17A (IL-17A) plays an essential role in tissue inflammation by inducing proinflammatory cytokine and chemokine production and is related to innate immune reactions. IL-17A also contributes to neuroinflammation, neuropathic pain, and mechanical hypersensitivity after peripheral nerve injury in rodents. To clarify the contribution of IL-17A to pain-related phenotypes in humans, we investigated the association between pain-related phenotypes and the rs2275913 single-nucleotide polymorphism (SNP) of the IL-17A gene, which has been reported to be associated with rheumatoid arthritis, ulcerative colitis, and some cancers. METHODS: The present study used a correlational design to examine the impact of the rs2275913 SNP on postoperative pain-related phenotypes in a group of patients who underwent cosmetic orthognathic surgery. RESULTS: Carriers of the AA genotype had higher opioid requirements during and after surgery than carriers of the AG and GG genotypes (P = .009). Linear regression analysis indicated that opioid requirements linearly increased as the copy number of the A allele of the SNP increased (P = .008). CONCLUSIONS: Opioid requirements during and after surgery are enhanced in carriers of the AA genotype of the rs2275913 SNP of the IL-17A gene, possibly through an enhancement of IL-17A function that induces inflammation that is related to the inflammatory pain stimulus.
30067713 [Neumatosis quística intestinal: reporte de un caso]. 2018 ANTECEDENTES: La neumatosis quística intestinal es una condición infrecuente, caracterizada por la formación de quistes de contenido gaseoso debajo de la mucosa y la serosa intestinales. CASO CLÍNICO: Mujer de 84 años, con antecedente de artritis reumatoide en tratamiento inmunosupresor, intervenida hace 2 años por neumoperitoneo, con diagnóstico de diverticulosis yeyunal y enfisema mesentérico, acude con cuadro de dolor abdominal difuso de 2 días de evolución, sin otra sintomatología. En la radiografía de abdomen se observa neumoperitoneo con elevación del hemidiafragma derecho y distensión de asas del intestino delgado. Ante la sospecha de perforación de víscera hueca se decide intervención quirúrgica, en la cual se diagnostica a la paciente de neumatosis quística intestinal. CONCLUSIÓN: La neumatosis quística intestinal es de causa desconocida, aunque en un elevado porcentaje de pacientes se ha visto asociada a enfermedades pulmonares obstructivas, enfermedades del tejido conectivo, inmunosupresión o enfermedades gastrointestinales. Se localiza más frecuentemente en el colon y el intestino delgado. Se diagnostica principalmente mediante pruebas de imagen (radiografía o tomografía computarizada). El tratamiento es conservador, realizándose intervención quirúrgica si existe sospecha de necrosis intestinal. Es difícil el diagnóstico diferencial con un neumoperitoneo por perforación de víscera hueca. BACKGROUND: Pneumatosis cystoides intestinalis is an infrequent condition, characterized by the formation of gaseous content cysts under the mucosa and intestinal serous. CLINICAL CASE: 84-year-old woman, with a history of rheumatoid arthritis under immunosuppressive treatment, operated 2 years ago by pneumoperitoneum, where she was diagnosed of jejunal diverticulosis and mesenteric emphysema, with diffuse abdominal pain of 2 days of evolution, without other symptoms. In abdominal radiography: pneumoperitoneum with elevation of right hemidiaphragm and distention of small intestine. Given the suspicion of perforation of the intestinal wall, surgical intervention was decided, in which the patient was diagnosed with pneumatosis cystoides intestinalis. CONCLUSION: Pneumatosis cystoides intestinalis has an unknown etiology, although in a high percentage of patients it has been associated with obstructive pulmonary pathologies, connective tissue diseases, immunosuppression or gastrointestinal diseases. It is located more frequently in the colon and small intestine. It is diagnosed mainly through imaging tests (radiography or computed tomography). The treatment is conservative, performing surgical intervention if there is suspicion of intestinal necrosis; being difficult the differential diagnosis with a pneumoperitoneum by perforation of hollow viscera..
29908939 Delivery system for budesonide based on lipid-DNA. 2018 Sep Budesonide is a hydrophobic glucocorticoid with high anti-inflammatory activity for the treatment of asthma, inflammatory bowel disease and rheumatoid arthritis. A micellar drug-delivery system based on lipid-DNA may provide a strategy to maximize its drug efficacy and reduce adverse effects. In this work, we report the use of lipid-DNAA (UU11mer), featuring two hydrophobic alkyl chains and forming micelles at a comparatively low critical micelle concentration, to render budesonide water-soluble with a high loading capacity (LC). The inhibition of interleukin-8 (IL-8) release shows that the new delivery system retains the inhibitory activity in cell-based assays. In conclusion, this research provides a novel approach to formulate and administer budesonide in a non-invasive manner, which dramatically improves its water-solubility while retaining its bioavailability.
29782009 Construction of Synthetic Phage Displayed Fab Library with Tailored Diversity. 2018 May 1 Demand for monoclonal antibodies (mAbs) in basic research and medicine is increasing yearly. Hybridoma technology has been the dominant method for mAb development since its first report in 1975. As an alternative technology, phage display methods for mAb development are increasingly attractive since Humira, the first phage-derived antibody and one of the best-selling mAbs, was approved for clinical treatment of rheumatoid arthritis in 2002. As a non-animal based mAb development technology, phage display bypasses antigen immunogenicity, humanization, and animal maintenance that are required from traditional hybridoma technology based antibody development. In this protocol, we describe a method for construction of synthetic phage-displayed Fab libraries with diversities of 10(9)-10(10) obtainable with a single electroporation. This protocol consists of: 1) high-efficiency electro-competent cell preparation; 2) extraction of uracil-containing single-stranded DNA (dU-ssDNA); 3) Kunkel's method based oligonucleotide-directed mutagenesis; 4) electroporation and calculation of library size; 5) protein A/L-based enzyme-linked immunosorbent assay (ELISA) for folding and functional diversity evaluation; and 6) DNA sequence analysis of diversity.
29776017 Pharmacokinetics and C-reactive protein modelling of anti-interleukin-6 antibody (PF-04236 2018 Sep AIMS: The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-interleukin-6 monoclonal antibody, and its pharmacokinetic/pharmacodynamic (PK/PD) relationship on serum C-reactive protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn's disease (CD). METHODS: Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from two phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study and a Phase 2 SLE study were included. RESULTS: A two-compartment model with first order absorption and linear elimination and a mechanism-based indirect response model adequately described the PK and PK/PD relationships, respectively. Central compartment volume of distribution (Vc) positively correlated with body weight. Clearance (CL) negatively correlated with baseline albumin concentration and positively correlated with baseline CRP and creatinine clearance, and was slightly lower in females. After correcting for covariates, CL in CD subjects was approximately 60% higher than other populations. Maximum inhibition of PF-04236921 on CRP production (I(max) ) negatively correlated with baseline albumin. I(max) positively correlated with baseline CRP and the relationship was captured as a covariance structure in the PK/PD model. CONCLUSION: Integrated population PK and PK/PD models of PF-04236921 have been developed using pooled data from healthy subjects and autoimmune patients. The current model enables simulation of PF-04236921 PK and PD profiles under various dosing regimens and patient populations and should facilitate future clinical study of PF-04236921 and other anti-interleukin-6 monoclonal antibodies.
29691171 Risk Adjustment Is Necessary in Medicare Bundled Payment Models for Total Hip and Knee Art 2018 Aug BACKGROUND: Concerns exist that high-risk patients in alternative payment models may face difficulties with access to care without proper risk adjustment. The purpose of this study is to identify the effect of medical and orthopedic specific risk factors on the cost of a 90-day episode of care following total hip (THA) and knee arthroplasty (TKA). METHODS: We queried the Medicare 5% Limited Data Set for all patients undergoing primary THA and TKA from 2010 to 2014. To evaluate the cost of an episode of care, we calculated all claims for 90 days following surgery. Multivariate analysis was performed to quantify the added episode-of-care costs for demographic variables, geography, medical comorbidities, and orthopedic specific risk factors. RESULTS: Of the 58,809 TKA patients, the median 90-day Medicare costs was $23,800 (interquartile range, $18,900-$32,300), while the median of the 27,293 THA patients was $24,000 (interquartile range, $18,500-$33,900). Independent risk factors (all P < .05) resulting in at least a 10% increase in episode-of-care costs following TKA included malnutrition, age over 85, male gender, pulmonary disorder, failed internal fixation, Northeast region, lower socioeconomic status, neurologic disorder, and rheumatoid arthritis. Independent risk factors (all P < .05) resulting in at least a 10% increase in episode-of-care costs following THA included malnutrition, male gender, age over 85, failed internal fixation, hip dysplasia, Northeast region, neurologic disorder, lower socioeconomic status, conversion THA, avascular necrosis, and depression. CONCLUSION: Certain comorbidities and orthopedic risk factors increase 90-day episode-of-care costs in the Medicare population. The current lack of proper risk stratification could be a powerful driver of decreased access to care for our most medically challenged members of society.
29517899 Photochemical Control of Protein Arginine Deiminase (PAD) Activity. 2018 Apr 20 Protein arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis, and breast cancer. Therefore, the development of PAD inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis isomer of 1 is 10-fold more potent than its trans isomer, whereas the trans isomer of 2 is 45-fold more potent than the corresponding cis isomer. The altered inhibitory potency upon photoisomerization has been confirmed in a competitive activity-based protein profiling (ABPP) assay. Further investigations indicate that the trans isomer of 2 is an irreversible inhibitor, whereas the cis isomer acts as a competitive inhibitor. In cells, the trans isomer of compound 1 is completely inactive, whereas the cis isomer inhibits histone H3-citrullination in a dose-dependent manner. Taken together, 1 serves as the foundation for developing photopharmaceuticals that can be activated at the desired tissue, using light, to treat diseases where PAD activity is dysregulated.
29275836 A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. 2018 Feb Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). Unlike the 'master regulators' T-bet and GATA3 that orchestrate Th1 and Th2 differentiation, respectively, RORγ controls transcription at relatively few loci in Th17 cells. Moreover, its expression is not stabilized by positive feedback loops but rather influenced by environmental cues, allowing for substantial functional plasticity. Importantly, a subset of IL-17/IFNγ double-producing Th17 cells was identified in both human and mouse models. Evidence is accumulating that these IL-17/IFNγ double-producing cells are pathogenic drivers in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, IL-17/IFNγ double-producing cells have been identified in disorders in which the role of autoimmunity remains unclear, such as sarcoidosis. The observed plasticity of Th17 cells towards the Th1 phenotype can be explained by extensive epigenetic priming of the IFNG locus in Th17 cells. In fact, Th17 cells display an IFNG chromatin landscape that is remarkably similar to that of Th1 cells. On the other hand, pathogenic capabilities of Th17 cells can be restrained by stimulating IL-10 production and transdifferentiation into IL-10 producing T regulatory type 1 (Tr1) cells. In this review, we discuss recent advances in our knowledge on the cellular and molecular mechanisms involved in Th17 differentiation, heterogeneity and plasticity. We focus on transcriptional regulation of the Th17 expression program, the epigenetic dynamics involved, and how genetic variants associated with autoimmunity may affect immune responses through distal gene regulatory elements. Finally, the implications of Th17 cell plasticity for the pathogenesis and treatment of human autoimmune diseases will be discussed.
29128174 Health-related quality of life in MEN1 patients compared with other chronic conditions and 2018 Jan BACKGROUND: Health-related quality of life (HRQOL) in multiple endocrine neoplasia type-1 (MEN-1) is poorly described. HRQOL in MEN-1 was compared with other chronic conditions and the US general population. METHODS: Adults aged ≥18 years recruited from an MEN-1 support group (n=153) completed the Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item profile. MEN-1 scores were compared with PROMIS scores reported in peer-reviewed literature from back pain (n=218), cancer (n=310), congestive heart failure (CHF; n=60), chronic obstructive pulmonary disease (COPD; n=79), major depressive disorder (n=196), rheumatoid arthritis (RA; n=521), neuroendocrine tumors (NET; n=619), and primary hyperparathyroidism (PHPT; n=45) cohorts. RESULTS: Patients with MEN-1 reported worse anxiety (mean=61.7), depression (57.9), fatigue (62.2), pain interference (55.4), sleep disturbance (58.0), physical functioning (44.4), and social functioning (44.7) compared to normative data (50, P < .05) and greater anxiety, depression, and fatigue than patients with back pain, cancer, COPD, RA, NETs, and PHPT (P < .001). MEN-1 respondents had greater pain interference (55.4) than those with cancer (51.9), NETs (52.3), and PHPT (38.4, P < .05). Physical functioning was higher in individuals with MEN-1 (44.4) than in those with back pain (37.5), CHF (34.8), COPD (38.0), and RA (40.7, P < .01). CONCLUSION: This is the first study to describe HRQOL in a large sample of adults with MEN-1. MEN-1respondents reported worse HRQOL across PROMIS 29-item profile measure domains compared with the US general population and higher levels of anxiety, depression, and fatigue compared with many other chronic conditions.
29042208 Antiallodynic activity of leflunomide is partially inhibited by naltrexone and glibenclami 2018 Jan 5 Leflunomide, an immunosuppressive drug approved for the treatment of patients with rheumatoid arthritis, exhibits many mechanisms which may affect the nociceptive processing. Therefore, the present study aimed to evaluate the effect induced by leflunomide on the mechanical allodynia in models of inflammatory and neuropathic pain in mice and investigate mechanisms mediating such effects. Per os (p.o.) administration of leflunomide (25, 50 or 100mg/kg) inhibited the inflammatory edema and mechanical allodynia induced by intraplantar carrageenan. Even ongoing inflammatory edema and mechanical allodynia were reduced by leflunomide. Previous administration of naltrexone (10mg/kg, intraperitoneal) or glibenclamide (40mg/kg, p.o.) partially attenuated leflunomide antiallodynic activity. A single administration of leflunomide (50 or 100mg/kg, p.o.) also partially inhibited ongoing mechanical allodynia induced by chronic constriction injury (CCI) or repeated administrations of paclitaxel. The antiallodynic effect induced by leflunomide (50 or 100mg/kg, p.o.) in the model of neuropathic pain induced by CCI was associated with reduced production of tumor necrosis factor-α both at the injury site and ipsilateral paw. Leflunomide also reduced production of the chemokine CXCL-1 at the paw ipsilateral to the injury site. Concluding, leflunomide partially inhibited ongoing mechanical allodynia in models of inflammatory and neuropathic pain. The antiallodynic effect was associated with activation of opioidergic receptors and ATP-sensitive potassium channels and reduced production of inflammatory mediators. These data indicate leflunomide as a drug that should be further investigated aiming to identify a new analgesic pharmacotherapy and reinforces repositioning as an important strategy to identify new uses for approved drugs.
28722163 Risk of cancer in patients with psoriasis on biological therapies: a systematic review. 2018 Jan BACKGROUND: Biological therapies are highly effective in psoriasis, but have profound effects on innate and adaptive immune pathways that may negatively impact on cancer immunosurveillance mechanisms. OBJECTIVES: To investigate the risk of cancer in patients with psoriasis treated with biological therapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Library (up to August 2016) for randomized controlled trials, prospective cohort studies and systematic reviews that reported cancer incidence in people exposed to biological therapy for psoriasis compared with a control population. RESULTS: Eight prospective cohort studies met our inclusion criteria. All the evidence reviewed related to tumour necrosis factor inhibitors (TNFi) with the exception of one study on ustekinumab. An increased risk of nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma, was reported with TNFi compared with both a general United States population and a rheumatoid arthritis population treated with TNFi. No evidence for increased risk of cancers (reported as all cancers, lymphoma, melanoma, prostate, colorectal and breast cancer) other than NMSC was identified. CONCLUSIONS: There were important limitations to the studies identified including choice of comparator arms, inadequate adjustment for confounding factors and failure to account for latency periods of cancer. There remains a need for ongoing pharmacovigilance in relation to cancer risk and biological therapy; the NMSC signal requires further investigation to determine the risk specifically attributable to biological therapy using prospectively collected data with adjustment for known NMSC risk factors.
28296250 Different genetic alteration of A20 in a Sézary syndrome case with Vα2-Jα22 T cell clon 2018 Apr BACKGROUND: The comprehensive genetic alterations underlying the pathogenesis of Sézary syndrome (SS) remains largely unknown. Previous studies showed that alterations of tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) are frequent in SS. In this study, we characterized the mutation and polymorphisms of A20 in a case with SS and compared with the genetic feature of A20 in T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Using a novel approach based on the combination of fine-tiling array comparative genomic hybridization ( and ligation-mediated polymerase chain reaction (LM-PCR) to identify SS clone, the polymorphisms in the A20 gene (promoter, exons 2-9 [coding region] and 3'UTR) were detected by PCR and sequencing. RESULTS: The malignant SS clone was identified as TCR Vα2-Jα22 rearrangement without deletion at the A20 loci (6q23-27 region) in the SS case. Six polymorphisms were identified, all of them are belonging to single nucleotide polymorphisms (SNPs) that are recorded in genebank: rs5029924, rs5029937, rs2230926, rs582757 and rs77191406, while rs2307859 was not identified in the SS sample, which is found in all T-ALL. The alteration pattern of A20 in this case seemed different from the T-ALL samples, in contrast, it is similar to the alteration of A20 in samples from rheumatoid arthritis or systemic lupus erythematosus with poor clinical outcome and cancer developing. CONCLUSIONS: The genetic alteration of A20 in the SS case was different from the T-ALL samples and similar to the cases with refractory autoimmune disease and related to tumorigenesis. The findings lead to discuss whether such SNPs of A20 may link the refractory autoimmune inflammation and the tumorigenesis.
30574739 Stimulated mast cells release inflammatory cytokines: potential suppression and therapeuti 2018 Nov Mast cells (MCs) are derived from bone marrow precursors and are immune cells involved in acute and chronic inflammation. MCs are ubiquitous and play a crucial role in innate and acquired immunity. They are activated through cross-linking of their surface high affinity receptors (FcεRI), leading to immediate secretion of stored inflammatory mediators, and late production and release of pro-inflammatory cytokines/chemokines without degranulation. Therefore, MCs are important in inflammatory responses. Members of the interleukin (IL)-1 cytokine family, such as IL-1 and IL-33, and various antigens markedly increase IL-1 and tumor necrosis factor (TNF) expression and secretion from MCs. One of the latest cytokines is IL-33, an IL-1 family member acting via its ST2/IL-1R4, which has been shown to regulate MCs. IL-1 and IL-33 are cytokines found to be implicated in many inflammatory disorders including rheumatoid arthritis, atherosclerosis and psoriasis. In general, IL-1 family member cytokines play a pro-inflammatory role and increase the pathological state. IL-37 is a member of the IL-1 family with anti-inflammatory activity through inhibition of pro-inflammatory cytokines. IL-37 particularly suppresses IL-1-mediated innate inflammatory response, but also acts on the acquired immune response. IL-37 is activated by pro-inflammatory agents and cytokines, playing a protective role against inflammation. This cytokine is a natural regulator of immunity and is a therapeutic promise against inflammatory diseases. Since IL-1 is produced by and activates MCs to release IL-33 and TNF, here we hypothesize that MCs can be inhibited by IL-37 and therefore reduce their pro-inflammatory activity. However, the maturation, transport and secretion of IL-37 remain to be clarified.
28625602 FRAX Score Can Be Used to Avoid Superfluous DXA Scans in Detecting Osteoporosis in Celiac 2018 Jul The Fracture Risk Assessment (FRAX) tool has been developed to estimate patients' 10-yr probability of fracture, thus establishing which patients should undergo dual-energy X-ray Absorptiometry (DXA) scan. This study aimed to evaluate if the FRAX tool can replace or optimize the use of DXA scan in celiac disease (CD). We prospectively enrolled all CD patients aged over 40 yr diagnosed at our third-level unit. At time of CD diagnosis, all patients underwent FRAX score calculation for risk of major osteoporotic and hip fractures and DXA scan (used as gold standard) to assess the accuracy of the FRAX score. The FRAX score calculation was based on the following 10 variables: age (>40 yr), sex (M/F), body mass index, history of previous fracture (yes/no), parent fractured hip (yes/no), current smoking (yes/no), use of steroids (yes/no), rheumatoid arthritis (yes/no), secondary osteoporosis (yes/no), and alcohol ≥3 units/d (yes/no). DXA assessment was performed within 1 week from FRAX calculation. The FRAX score was dichotomized as normal or pathologic in accordance with the National Osteoporosis Guideline Group. A total of 160 CD patients were enrolled (M/F = 20/140; mean age 48.7 yr). A pathologic FRAX score was evident in 14 out of 160 patients (8.7%), whereas osteoporosis based on DXA scan was found in 10 patients (6%) (κ = 0.6); 3 patients with osteoporosis (1.9%) showed a 10-yr risk of major fracture >10% according to the National Osteoporosis Guideline Group criteria. With regard to diagnostic accuracy, the FRAX score showed sensitivity of 0%, specificity of 91%, positive predictive value of 0%, and negative predictive value of 94%. The prevalence of osteoporosis in adult CD appears to be quite low and only a small proportion of patients would require a DXA investigation. The FRAX score could be an effective tool to avoid useless DXA scans in CD patients in view of its high negative predictive value.