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ID PMID Title PublicationDate abstract
27533304 Risk Factors of (131)I-Induced Salivary Gland Damage in Thyroid Cancer Patients. 2016 Nov CONTEXT: Sialadenitis and xerostomia are major adverse effects of (131)I therapy in thyroid cancer patients. The risk factors for these adverse effects, other than administered activity of (131)I, have not been investigated. OBJECTIVE: The aim of this study is to identify risk factors for (131)I-induced salivary gland damage among follicular cell-derived thyroid cancer patients. DESIGN: We enrolled 216 thyroid cancer patients who visited The Ohio State University Wexner Medical Center between April 2013 and April 2014. Symptoms of xerostomia and sialadenitis were identified via questionnaire and medical record search. To validate the findings in a large cohort, we retrospectively searched for ICD-9/10 codes for sialadenitis, xerostomia, and autoimmune disease associated with Sjögren's syndrome (AID-SS) in our existing database (n = 1507). Demographic and clinical information was extracted from medical records. Multivariate analyses were performed to identify independent predictors for salivary gland damage. RESULTS: (131)I treatment associated with higher incidence of xerostomia and sialadenitis. Patients with xerostomia had 46 mCi higher mean cumulative (131)I activity and 21 mCi higher mean first-administered (131)I activity than patients without xerostomia. Increased age associated with higher incidence of xerostomia, and females had a higher incidence of sialadenitis. Patients who experienced sialadenitis before (131)I therapy had higher sialadenitis incidence after (131)I therapy. (131)I-treated patients diagnosed with AID-SS, whether before or after (131)I treatment, had a higher incidence of xerostomia and sialadenitis among (131)I-treated patients. CONCLUSION: Risk factors for (131)I-induced salivary gland damage include administered (131)I activity, age, gender, history of sialadenitis before (131)I treatment, and AID-SS diagnosis.
27517517 Clinical and immunological consequences of total glucosides of paeony treatment in Sjögre 2016 Oct BACKGROUND: The total glucosides of paeony (TGP) can inhibit inflammation and alleviate symptoms in autoimmune diseases. This study investigated the clinical and immunological consequences of TGP treatment in patients with primary Sjögren's syndrome (SS). METHODS: We conducted a randomized, double-blinded, placebo-controlled clinical trial in 45 patients with primary SS. Patients were randomized at 2:1 ratio to either TGP group (n=29) or placebo group (n=16) and followed up for 24weeks. The primary outocme was the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index (ESSPRI). The secondary outcomes were stimulated and unstimulated salivary flow rate, Schirmer's test and erythrocyte sedimentation rate (ESR), immuneglobulin (Ig), anti-nuclear antibody (ANA), anti-SSA, and anti-SSB. The proportions of B cells in peripheral blood and the levels of serum inerleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and B cell activating factor belonging to the TNF family (BAFF) were measured at baseline and at the end of follow up of 24weeks. RESULTS: The average score of ESSPRI in both groups had no statistical significance at 24th week. The mean of ESSPRI in the dry-mouth part of questionnaire in patients who scored 3 to 6 points was significantly reduced in the TGP group changed from (4.81±0.60) at baseline to (4.20±1.46) (P=0.027) at week 24. Stimulated salivary flow rate increased at week 24 from (1.80±0.39) to (2.01±0.51) (P=0.031) and unstimulated salivary flow rate increased from (0.65±0.46) to (0.78±0.45) (P=0.011) in the TGP group, but the placebo group showed no significant difference. Erythrocyte sedimentation rate (ESR) was decreased significantly compared to the placebo group at 12- and 24-week from (40.9±18.0) to (29.4±12.2) (P=0.003) and (30.4±17.3) (P=0.024). The percentage of naive B cells decreased at week 24 in the TGP group from (77.34±12.20) to (64.59±15.60) (P=0.005) while memory B cells increased from (21.79±11.97) to (34.21±15.48) (P=0.006) respectively. The concentrations of TNF-α and IFN-γ decreased in the TGP group at week 24 from (32.51±26.67) to (24.22±13.56) (P=0.017) and (10.71±8.94) to (6.55±4.88) (P=0.022), respectively. No significant difference in ANA titer, anti-SSA antibodies, anti-SSB antibodies, C3 concentration or C4 concentration was observed between the two groups. CONCLUSION: TGP appears to improve the glandular secreting function and decrease the level of inflammatory cytokines.
26358223 A comprehensive investigation on the distribution of circulating follicular T helper cells 2016 Jan Follicular T helper (Tfh) cells have a crucial role in regulating immune responses within secondary lymphoid follicles by directing B cell differentiation towards memory B cells and plasma cells. Because abnormal humoral responses are key features in both primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE), the aim of this study was to profile the pathological connection between peripheral Tfh cells and B cells in the two diseases. Twenty-five pSS patients, 25 SLE patients and 21 healthy controls were enrolled into the study. We determined the ratio of circulating Tfh-like cells, their interleukin (IL)-21 production and different B cell subsets by flow cytometry. We observed higher percentages of naive B cells in both diseases, while non-switched and switched memory B cells showed decreased frequencies. The proportions of double-negative B cells and plasmablasts were elevated in SLE and decreased in pSS. The percentages of transitional B cells and mature-naive B cells were higher in SLE. Patients with more severe disease course had an elevated ratio of TFH-like cells and increased IL-21 production. Moreover, expansion of Tfh-like cells correlated positively with parameters related to antibody secretion, including serum immunoglobulin (Ig)G, immune complexes (ICs) and autoantibodies. Correlation analysis between Tfh-like cells and certain B cell subsets revealed possible defects during B cell selection. In conclusion, our observations on the profound expansion of circulating Tfh-like cells and their IL-21 production, along with the characteristic aberrant peripheral B cell distribution in both pSS and SLE, indicate the prominent role of Tfh cell in the regulation of B cell selection.
26582440 Long-term Sequelae of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. 2016 May Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions characterized by different extents of epidermal necrosis and mucosal breakdown. A limited number of studies have reported the long-term patterns of SJS and TEN complications in patient populations over long follow-up periods. The aim of this retrospective study was to collect data on long-term sequelae in patients admitted for SJS, SJS/TEN overlap, or TEN between 1998 and 2012. Among all 102 patients eligible for analysis, the 2 most common sequelae were cutaneous and ocular problems, both with incidences of 44.1%. Visceral organ involvement was observed in 2 patients with irreversible deterioration of chronic kidney disease and in one patient with interstitial lung disease. Autoimmune disease was present in 6 patients: Sjögren's syndrome or Sjögren-like syndrome in 5 patients and concomitant systemic lupus erythematosus and Hashimoto thyroiditis in one patient.
26113358 Ro/SSA autoantibody-positive pregnancy: reactions to serial fetal Doppler echocardiographi 2015 Dec OBJECTIVE: The risk for congenital heart block (CHB) associated with maternal Ro/SSA autoantibodies is low, but the possibility of treating early stages of disease has seen the introduction of Doppler echocardiographic surveillance programs with serial examinations during the CHB susceptibility weeks of pregnancy. The aim of the present study was to understand how Ro/SSA autoantibody-positive women having undergone Doppler echocardiographic surveillance programs and giving birth to children without CHB experienced their pregnancy and frequent ultrasound examinations. METHODS: A validated questionnaire based on data from an interview-study was distributed to Ro/SSA-positive women supervised with Doppler examinations during their pregnancy (n = 100). RESULTS: The response rate was 79%. The majority of the women (61%) reported that the increased number of ultrasound examinations influenced their pregnancy, but in a positive way, with qualified information and additional support from health care personnel in conjunction with the examinations. Further, the visits to the clinic provided opportunities to see the ultrasound picture of the expected infant. However, one-third of the women also reported stress in relation to the examinations. CONCLUSIONS: Fetal echocardiographic surveillance holds many and predominantly positive effects for Ro/SSA-positive women during pregnancy in addition to the medical advantages.
25354755 Prevalence of distal renal tubular acidosis in primary Sjögren's syndrome. 2015 May OBJECTIVES: Our objectives were to analyse the prevalence of distal renal tubular acidosis (dRTA) in primary SS (pSS) and to compare a novel urinary acidification test with furosemide and fludrocortisone (FF) with the gold standard ammonium chloride (NH4Cl) to detect dRTA. METHODS: Urinary acidification was assessed in 57 pSS patients using NH4Cl and FF. A urinary acidification defect was defined as an inability to reach a urinary pH of <5.3 after NH4Cl. RESULTS: The prevalence of complete dRTA (urinary acidification defect with acidosis) was 5% (3/57). All three patients had positive SSA/Ro and SSB/La autoantibodies and impaired kidney function. The prevalence of incomplete dRTA (urinary acidification defect without acidosis) was 25% (14/57). Compared with patients without dRTA, patients with incomplete dRTA had significantly lower venous pH and serum bicarbonate and higher urinary pH. SSB/La antibodies were more prevalent in the dRTA groups (P < 0.05). Compared with NH4Cl, the positive and negative predictive values of FF were 46% and 82%, respectively. Vomiting occurred more often during the urinary acidification test with NH4Cl than with FF (9 vs 0, P < 0.05). CONCLUSION: Incomplete dRTA is common in pSS and causes mild acidaemia and higher urinary pH, which may contribute to bone demineralization and kidney stone formation. FF cannot replace NH4Cl in testing urinary acidification in pSS, but may be considered as a screening tool, given its reasonable negative predictive value and better tolerability.
25190637 Characterization of circulating endothelial microparticles and endothelial progenitor cell 2015 Mar OBJECTIVE: Chronic autoimmune diseases are associated with increased risk of cardiovascular death. Endothelial dysfunction represents the first stage of subclinical atherosclerosis and multiple factors contribute to endothelial injury. Among these, an altered balance between endothelial microparticle (EMP) release and endothelial progenitor cell (EPC) generation promotes endothelial dysfunction. The role of EMPs and EPCs in promoting endothelial damage in primary SS (pSS) has never been investigated. Our aim was to evaluate the role of EMPs and EPCs as markers of endothelial damage in pSS and their correlation with disease clinical and immunological features. METHODS: Circulating EMPs (CD31(+)/CD42(-)), true EPCs (CD34(+)/KDR(+)/CD133(+)) and mature EPCs (CD34(+)/KDR(+)/CD133(-)) were quantified by FACS analysis in 34 pSS patients and 18 age- and sex-matched controls. Correlation between EMP and EPC levels and parameters of disease activity and damage, clinical features and markers of immunological dysfunction was performed. RESULTS: Patients displayed higher EMP numbers with respect to healthy controls [HCs; mean 450 n/μl (S.D. 155) vs 231 (110), P < 0.0001]. EPC and mature EPC levels were higher in patients compared with HCs [mean 226 n/ml (S.D. 181) vs 69 (53), P < 0.001 and 166 (161) vs 36 (32), P < 0.0001, respectively). EMP levels directly correlated with disease duration from symptoms and diagnosis (ρ = 0.5, P < 0.01). Early EPCs inversely correlated with disease duration from symptoms (ρ = -0.5, P < 0.01) and diagnosis (ρ = -0.4, P < 0.05). CONCLUSION: This is the first demonstration of chronic endothelial fragmentation characterizing pSS. The reparative potentiality of the endothelial layer appears to be preserved in the earliest stages of disease. During the course of the disease, progressive exhaustion of the precursor endothelial pool may be hypothesized, leading to defective vascular layer restoration and endothelial dysfunction.
25036233 Usefulness of tacrolimus for refractory adult-onset still's disease: Report of six cases. 2016 Nov Six patients with refractory adult-onset Still's disease (AOSD) were treated with tacrolimus (TAC). Patient 1 was pregnant, for whom high-dose corticosteroid (CS) monotherapy did not achieve clinical remission, whereas TAC concomitant with CS was successful, and her baby had no apparent abnormalities. Patient 2 had hemophagocytic syndrome (HPS), for whom high-dose CS monotherapy did not achieve clinical remission, whereas TAC improved HPS, and a complete clinical remission was achieved with concomitant administration of TAC and methotrexate (MTX) with CS. Cases 3-5 could not have reduced CS doses due to repeated recurrences and other disease-modifying antirheumatic drugs, including MTX, Cyclosporine A, and tumor necrosis factor alpha inhibitors, did not control disease activity. TAC administration allowed for reduced CS doses. Case 6 experienced adverse effects, and TAC was discontinued due to elevated serum creatinine and potassium levels. TAC was useful for five of six patients, which suggests it as an option for refractory AOSD.
26882171 Comprehensive epidemiological and genotype-phenotype analyses in a large European sample w 2016 Jun BACKGROUND AND AIM: Although an eight-residue insertion in HLA-DQβ1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS: We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQβ1 insertion carriers and noncarriers. RESULTS: Our data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren's syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQβ1 insertion carriers (P=0.031). CONCLUSION: Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQβ1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.
25582848 The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules are asso 2015 Feb Primary Sjögren's syndrome (pSS) is associated with HLA-DRB1 loci, but the association of amino acid variations in the hypervariable region of the HLA-DR β1 chain with pSS is largely unknown. In this study, we aimed to identify the amino acid variations within the hypervariable region of HLA-DRB1 molecule which are associated with the susceptibility to pSS. We sequenced the 2nd exon of the HLA-DRB1 locus in 52 pSS patients and 179 controls. The HLA-DRB1*0803 is the allele that shows the strongest association with pSS in Chinese population (OR = 3.0, P = 2.4 × 10(-4)). Furthermore, amino acid variations within the binding pocket P7 and P9 are associated with the susceptibility to pSS. An interaction between two residues within P7, β47 and β67, is associated with pSS. Structural modeling studies demonstrated that the electrostatics of peptide binding pocket 9 are opposite in pSS-susceptible and -protective HLA-DRB1 alleles. In conclusion, our results suggest that structural heterogeneity of the HLA-DRB1 peptide binding pocket P7 and P9 might play a role in the pathogenesis of pSS.
26687745 Radical scavenging, antioxidant, and cytotoxic activities of the methanolic extracts from 2015 Nov Ternstroemia pringlei (Rose) Standl. (Theaceae) is widely used in Mexican traditional medicine to treat a diverse array of illnesses including rheumatoid pains, and is listed as one of the most consumed medicinal plants in the country. We selected T. pringlei given the strong relationship between oxidative stress and arthritis pathology, and investigated antioxidant potential of leaf, petal, fruit and seed methanolic extracts. Our method included assessing the in vitro free radical scavenger activity using the 2,2´-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) test, as well as the in vivo antioxidant action in the H2O2 protection model with Saccharomyces cerevisiae. Leaves and fruits afforded the most active extract in the ABTS assay, with antiradical activity of IC50=33.91 and 38.09μg/mL, respectively; while fruit extracts at 250μg/mL proved the most protective action against H2O2 oxidative stress. All extracts were non-cytotoxic against HF-6 (colon), PC-3 (prostate), MCF-7 (breast), SiHa (cervical) cancer cell lines and also toward the HFS-30 fibroblast normal skin cell line (IC50&>20μg/mL). Leaf methanolic extracts afforded ternstroside B, a known phenylethanoid glycoside with a strong free radical scavenging action. The presence of this kind of metabolites opens new research perspectives for the plant.
26935903 EAF2 mediates germinal centre B-cell apoptosis to suppress excessive immune responses and 2016 Mar 3 Regulated apoptosis of germinal centre (GC) B cells is critical for normal humoral immune responses. ELL-associated factor 2 (EAF2) regulates transcription elongation and has been shown to be an androgen-responsive potential tumour suppressor in prostate by inducing apoptosis. Here we show that EAF2 is selectively upregulated in GC B cells among various immune cell types and promotes apoptosis of GC B cells both in vitro and in vivo. EAF2 deficiency results in enlarged GCs and elevated antibody production during a T-dependent immune response. After immunization with type II collagen, mice lacking EAF2 produce high levels of collagen-specific autoantibodies and rapidly develop severe arthritis. Moreover, the mutant mice spontaneously produce anti-dsDNA, rheumatoid factor and anti-nuclear antibodies as they age. These results demonstrate that EAF2-mediated apoptosis in GC B cells limits excessive humoral immune responses and is important for maintaining self-tolerance.
26634249 High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated wi 2015 Dec 4 BACKGOUND: The formation of bony spurs and ankylosis is a key pathognomic feature in ankylosing spondylitis (AS) and results in functional impairment. The aim of this study was to investigate the role of IL-32γ in osteoblast (OB) differentiation and its association with the pathogenesis of AS. METHODS: The concentration and expression of IL-32γ were evaluated in synovial fluid and tissue from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA), using enzyme-linked immunosorbent assay and immunohistochemistry. To establish whether IL-32γ affects OB differentiation, we used calvarial cells of IL-32γ transgenic (TG) mice or wild-type (WT) mice. To elucidate the mechanism of osteoblastogenesis, levels of regulators were assayed in IL-32γ TG mice and in primary OBs after IL-32γ stimulation. RESULTS: The IL-32γ levels were higher in the synovial fluid of AS patients compared with RA or OA patients and the expression of IL-32 was higher in AS synovia than in RA or OA synovia. Additional IL-32γ stimulation in precursor cells enhanced OB differentiation potentially and IL-32γ TG mice showed higher rates of OB differentiation than WT mice. IL-32γ reduced the expression of DKK-1, a negative regulator, in both WT precursor cells and human OBs and the constitutive expression of DKK-1 was suppressed in calvarial cells from IL-32γ TG mice. CONCLUSIONS: The elevated level of IL-32γ in AS joint could enhance OB differentiation via DKK-1 suppression. Therefore, IL-32γ might be a putative molecular target to prevent the abnormal bone formation in AS.
25889265 Detecting cathepsin activity in human osteoarthritis via activity-based probes. 2015 Mar 20 INTRODUCTION: Lysosomal cathepsins have been reported to contribute to Osteoarthritis (OA) pathophysiology due to their increase in pro-inflammatory conditions. Given the causal role of cathepsins in OA, monitoring their specific activity could provide means for assessing OA severity. To this end, we herein sought to assess a cathepsin activity-based probe (ABP), GB123, in vitro and in vivo. METHODS: Protein levels and activity of cathepsins B and S were monitored by immunoblot analysis and GB123 labeling in cultured primary chondrocytes and conditioned media, following stimuli with tumor necrosis factor alpha (TNFα) and/or Interleukin 1 beta (IL-1β). Similarly, cathepsin activity was examined in sections of intact cartilage (IC) and degraded cartilage (DC) regions of OA. Finally, synovial fluid (SF) and serum from donors with no signs of diseases, early OA, late OA and rheumatoid arthritis (RA) patients were analyzed with GB123 to detect distinct activity levels of cathepsin B and S. RESULTS: Cathepsin activity in cell lysates, conditioned media explants and DC sections showed enhanced enzymatic activity of cathepsins B and S. Further histological analysis revealed that cathepsin activity was found higher in superficial zones of DC than in IC. Examining serum and SF revealed that cathepsin B is significantly elevated with OA severity in serum and SF, yet levels of cathepsin S are more correlated with synovitis and RA. CONCLUSIONS: Based on our data, cathepsin activity monitored by ABPs correlated well with OA severity and joint inflammation, directing towards a novel etiological target for OA, which possesses significant translational potential in developing means for non-invasive detection of early signs of OA.
28131664 Survival and outcomes after lung transplantation for non-scleroderma connective tissue-rel 2017 Jul BACKGROUND: Patients with non-scleroderma connective tissue-related lung disease (NS-CTLD), including rheumatoid arthritis, idiopathic inflammatory myopathies, Sjögren syndrome, mixed connective tissue disease, and systemic lupus erythematosus, may be at risk for worse outcomes after lung transplantation because of immune dysregulation or extrapulmonary manifestations of their underlying disease. We compared survival, acute and chronic rejection, and extrapulmonary organ dysfunction after transplantation in patients with NS-CTLD and idiopathic pulmonary fibrosis (IPF). METHODS: This was a retrospective cohort study of patients with NS-CTLD and IPF who were listed in the Scientific Registry of Transplant Recipients and underwent lung transplantation from May 5, 2005, to March 1, 2016. RESULTS: Patients with NS-CTLD (n = 275) were younger, a higher percentage female and non-white than patients with IPF (n = 6,346). NS-CTLD patients did not have worse adjusted survival (hazard ratio, 1.14, 95% confidence interval [CI], 0.92-1.42; p = 0.24). They were not more likely to have an episode of acute cellular rejection (odds ratio, 0.96; 95% CI, 0.72-1.28; p = 0.77) or to develop bronchiolitis obliterans syndrome (odds ratio, 0.82; 95% CI, 0.60-1.12; p = 0.21). Patients with NS-CTLD were not more likely to require plasmapheresis or dialysis or to develop a lymphoproliferative malignancy or liver disease after transplantation. CONCLUSIONS: We found no significant differences in survival, acute or chronic rejection, or extrapulmonary organ dysfunction in patients who underwent lung transplantation for NS-CTLD compared with IPF. In appropriately selected candidates, NS-CTLD should not be considered a contraindication to lung transplantation.
28064083 Identification of novel PAD4 inhibitors based on a pharmacophore model derived from transi 2017 Mar 1.4 Protein arginine deiminases 4 (PAD4) is an attractive target for the development of novel and selective inhibitors of Rheumatoid Arthritis (RA). F-amidine is known as mechanism-based inhibitor targeting PAD4 and used as inactivators by covalently modifying the active site Cys645. To identify novel structural inhibitors of PAD4, we investigated the flexibility of protein on basis of the transition state geometry of PAD4 inhibited by F-amidine from our previous QM/MM calculation. And a pharmacophore model was generated containing four features (ADHH) using five representative structures from molecular dynamic (MD) simulation on basis of the transition state geometry of PAD4 inhibited by F-amidine. We performed virtual screening using the pharmacophore model and molecular docking methods, resulting in the discovery of two molecules with K(D) (dissociation equilibrium constant) values of 112μM and 218μΜ against PAD4 through Surface Plasmon Resonance (SPR) experiments. These two molecules could potentially serve as PAD4 inhibitors.
28038706 Hepatosplenic T-cell lymphoma arising in patients with immunodysregulatory disorders: a st 2017 Feb Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that can arise in patients with underlying immune disorders. Others have suggested that tumor necrosis factor (TNF)-α inhibitor therapy for immune disorders increases the risk of HSTCL. To assess for a potential relationship between HSTCL and the use of TNF-α inhibitors, we searched for patients with HSTCL and underlying immune disorders at our institution. We identified 7 patients with a median age of 38 years. Five patients had Crohn disease, 1 ulcerative colitis, and 1 rheumatoid arthritis. In 6 patients, medication history for the immune disorder was available: 6 patients received 6-mercaptopurine or azathioprine, and 2 patients received steroids; no patients received TNF-α inhibitors. In all 7 patients, the histologic, immunophenotypic, and cytogenetic findings were similar to cases of HSTCL that arise in immunocompetent patients. We reviewed the literature and identified 60 patients with immune disorders who subsequently developed HSTCL. These patients were treated with immunosuppressive drugs in 89%, TNF-α inhibitors in 56%, and both therapies in 54%, and 1 (2%) patient was treated with TNF-α inhibitors only. Our cohort and literature review indicates that TNF-α inhibitor therapy is not essential for the development of HSTCL in patients with immunodysregulatory disorders, and implies that immunosuppressive drugs or other factors (eg, genetic predisposition, chronic antigenic stimulation) may be more critical in the pathogenesis in this context. Although these data are observational, they have implications for the use of TNF-α inhibitors in patients with inflammatory bowel disease and other immunodysregulatory disorders.
27583770 Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H 2016 Oct 13 Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
27550314 Ethanolic extract of Schizonepeta tenuifolia attenuates osteoclast formation and activatio 2016 Aug 22 BACKGROUND: Excessive osteoclast activity is a major cause of metabolic bone disorders, such as osteopenia, rheumatoid arthritis, and osteoporosis. Thus, discovery of agents targeting osteoclast differentiation and bone resorption is important for development of novel treatments for bone diseases. It has been demonstrated that ethanolic extract of schizonepeta tenuifolia (EEST) has potent anti-oxidant and anti-inflammatory activities. However, the beneficial effects of EEST on bone metabolism have not been studied. Therefore, we intend to investigate the effects of EEST on osteoclast differentiation. METHODS: We examined the effects and mechanisms of action of the EEST on osteoclastogenesis in vitro in bone marrow macrophages (BMMs) stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL) and in vivo using a mouse model of lipopolysaccharide (LPS)-induced bone destruction. RESULTS: We found that EEST inhibited phosphorylation of Akt and IkB at early stages of RANKL-induced osteoclastogenesis. Furthermore, EEST negatively controlled the transcription and translation levels of nuclear factor of activated T cells c1 (NFATc1) and the translation level of c-Fos at the final stage of osteoclast differentiation. Reflecting these effects, EEST blocked both filamentous actin (F-actin) ring formation and bone resorbing activity of mature osteoclasts in vitro. The inhibitory effects of EEST on osteoclast formation and activity were observed in an LPS-mediated bone erosion mouse model using micro-CT and histological analysis. CONCLUSIONS: EEST is a potential agent that is able to treat osteoclast-related bone diseases, such as osteoporosis.
27310969 Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet diseas 2016 Jun Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD patients, resulting in the improvement of clinical symptoms, CRP levels, and visual analogue scale score. Safety and pharmacokinetics profiles were comparable to those in patients with rheumatoid arthritis or Crohn disease. These findings support IFX as a new therapeutic option for patients with intestinal BD, NBD, or VBD.