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ID PMID Title PublicationDate abstract
27044355 Potential of sulfasalazine as a therapeutic sensitizer for CD44 splice variant 9-positive 2016 May Cancer stem-like cells (CSCs) with high expression of CD44 splice variant (CD44v) have an enhanced capacity for intracellular reduced glutathione synthesis and defense against reactive oxygen species, resulting in resistance to various therapeutic stresses. Sulfasalazine (SSZ), a drug used in the treatment of rheumatoid arthritis (RA), inhibits glutamate-cystine transport, and suppressed CD44v-dependent tumor growth and increased sensitivity to cytotoxic drugs in an in vivo study. Here, we present two cases of CD44v9-positive urogenital cancer with concomitant treatment with SSZ for RA. Patient 1 was a 62-year-old man who had received SSZ for RA beginning 2 months before the diagnosis of urinary bladder cancer. Although he had multiple metastases to the bladder, abdominal, left cervical and left axillary lymph nodes, and brain, complete response with multidisciplinary therapy was maintained for more than 2 years. Patient 2 was a 74-year-old man with castration-resistant prostate cancer who was diagnosed with RA during chemotherapy and a gradual increase in prostate-specific antigen (PSA) level. When SSZ was added, his PSA value (ng/mL) decreased from 12.93 to 5.58 in only 2 weeks and then quickly rebounded, whereas levels of neuron-specific enolase, a neuroendocrine differentiator and CSC marker, remained almost unchanged. We therefore speculate that SSZ treatment may represent a new adjuvant treatment option for patients with CD44v9-positive urogenital cancer.
26458738 Patients with ankylosing spondylitis have been breast fed less often than healthy controls 2016 May OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and pelvis of young adults. On the HLA-B27 genetic background, the occurrence of AS is influenced by the intestinal microbiota. The goal of our study was to test whether breast feeding, which influences microbiota, can prevent the development of AS. METHODS: First, 203 patients with HLA-B27-positive AS fulfilling the modified New York criteria were recruited in the Department of Rheumatology, Ste Marguerite hospital in Marseilles. A total of 293 healthy siblings were also recruited to make up a control group within the same families. Second, 280 healthy controls, and 100 patients with rheumatoid arthritis and their siblings were recruited. The data collected were age, gender, number of brothers and sisters, age at disease onset, type and duration of feeding (breast or bottle). RESULTS: Patients with AS had been breast fed less often than healthy controls. In families where children were breast fed, the patients with AS were less often breast fed than their healthy siblings (57% vs 72%), giving an OR for AS onset of 0.53 (95% CI (0.36 to 0.77), p value=0.0009). Breast feeding reduced familial prevalence of AS. The frequency of breast feeding was similar in the AS siblings and in the 280 unrelated controls. However, patients with AS were less often breast fed compared with the 280 unrelated controls (OR 0.6, 95% CI (0.42 to 0.89), p<0.01). CONCLUSIONS: Our study suggests a breastfeeding-induced protective effect on the occurrence of AS. To our knowledge, this is the first study of breastfeeding history in patients with AS.
26165391 Gastroprotective efficacy and safety of single-tablet ibuprofen/famotidine vs ibuprofen in 2015 Jul OBJECTIVES: A combination tablet of ibuprofen 800 mg and famotidine 26.6 mg given three times daily is effective for the treatment of rheumatoid arthritis and osteoarthritis and decreases the risk of developing upper gastrointestinal (GI) ulcers. This analysis evaluated the gastroprotective efficacy and safety of the single-tablet combination of ibuprofen/famotidine compared with ibuprofen alone on the basis of age and the presence of one or more risk factors for development of upper GI ulcer. METHODS: Pooled data from the 24-week, randomized, double-blind, parallel-group REDUCE-1 and REDUCE-2 trials were used. Endoscopies were performed in patients aged 40-80 years. The proportion of patients who developed ≥ 1 upper GI ulcer during treatment with ibuprofen/famotidine versus ibuprofen alone stratified on the basis of age (< 60 or ≥ 60 years) was evaluated. Further, analyses were performed on additional risk factors for ulcer development. RESULTS: Gastroprotective efficacy of the combination was not affected by age. Pooled results demonstrated statistically significantly fewer upper GI (10.0 vs 19.5%, p < 0.0001), gastric (8.9 vs 16.8%, p = 0.0004), and duodenal ulcers (1.1 vs 5.4%, p < 0.0001) in patients < 60 years treated with ibuprofen/famotidine versus ibuprofen alone compared with 12.9 vs 26.6% (p = 0.0002), 11.9 vs 23.4% (p = 0.0011), and 1.0 vs 4.5% (p = 0.0096), respectively, in patients ≥ 60 years. The ibuprofen/famotidine combination provided nearly 51 and 59% reduction in the risk of developing a GI ulcer in patients <60 years and ≥ 60 of age, respectively. Efficacy was maintained in the presence of additional risk factors, as well. CONCLUSIONS: These results indicate that the fixed-combination of ibuprofen/famotidine provides gastroprotection in those of older age, with or without additional risk factors for the development of upper GI ulcers, as compared with ibuprofen alone. US National Institutes of Health registry, http://www.clinicaltrials.gov, NCT00450658 and NCT00450216.
26513525 Amyloid-associated Cystic Lung Disease. 2016 May BACKGROUND: Amyloid-associated cystic lung disease is rare. It can be associated with collagen vascular disease (CVD). We aimed to describe the clinical, radiology, and pathology findings of this entity. METHODS: We reviewed the records of subjects having biopsy-proven pulmonary amyloidosis with cystic lung disease demonstrated at high-resolution computed tomography (HRCT). Demographic characteristics, association with CVD and lymphoproliferative disorders, pulmonary function, and pathology results were reviewed. HRCT appearance was analyzed for number, size, distribution, and morphology of cysts and nodules. RESULTS: Twenty-one subjects (13 female, eight male; median age, 61 years) with cystic pulmonary amyloidosis were identified. The most common pulmonary function patterns were normal (42%) and obstructive (32%). The most common associated CVD was Sjögren syndrome (10 of 12). Nine subjects had no CVD. Cysts tended to be multiple (≥ 10 in 14 of 21, 67%), round (21 of 21, 100%), or lobulated (20 of 21, 95%); thin-walled (< 2 mm in 17 of 21, 81%); and of small (< 1 cm in 21 of 21, 100%) to moderate (1-2 cm in 17 of 21, 81%) size. Peribronchovascular (19 of 21, 90%) and subpleural (19 of 21, 90%) cysts were typically present. Seventeen (81%) subjects had lung nodules, which tended to be numerous (≥ 10 in 10 of 17, 59%; 4-9 in six of 17, 35%). At least one calcified nodule was present in 14 of 17 subjects (82%). Pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) was diagnosed in seven subjects (33%). CONCLUSIONS: Amyloid-associated cystic lung disease can occur with or without underlying CVD. Cystic lesions in the lung are commonly numerous, often are peribronchovascular or subpleural, and are frequently associated with nodular lesions that are often calcified. MALToma was a relatively frequent association.
25422506 Systemic lentivirus-mediated delivery of short hairpin RNA targeting calcium release-activ 2015 Jan 1 Immune cells, including T cells, B cells, and osteoclasts, in conjunction with their associated cytokines, have been studied as primary molecular therapeutic targets for the management of rheumatoid arthritis (RA) patients. The increase in cytosolic Ca(2+) levels through the activation of store-operated Ca(2+) release-activated channels (CRACs) is involved in mediating a disparate array of cellular responses by these immune cells. This study was undertaken to investigate the feasibility and efficiency of the regulation of Ca(2+) entry in the treatment of RA. To moderately suppress Ca(2+) entry via CRACs, we gene silenced CRACM3, which was induced by systemic application of specific short hairpin RNAs (shRNAs) using a lentiviral-delivery system, in a murine model of collagen-induced arthritis (CIA). The inflammatory responses were determined by measuring the levels of a panel of cytokines and chemokines in the joints and serum. Ag-specific responses were evaluated by determining the cytokine profile of T cells stimulated with autoantigen. We also analyzed the ability of specific CRACM3-shRNA to regulate mature osteoclast function in CIA mice. The therapeutic effect of lentiviral-delivered CRACM3-shRNA was associated with gene silencing of CRACM3, along with the successful biodistribution of the virus. Extracellular Ca(2+) influx in the splenocytes, thymocytes, and knee joint synovial cells was moderately suppressed. Inflammatory responses and autoimmune responses were reduced by CRACM3 gene silencing. A decrease in mature osteoclast activity also was observed in CRACM3-shRNA-treated CIA mice. These results indicate that regulation of Ca(2+) entry through lentivirus-mediated CRACM3 gene silencing is beneficial in the treatment of RA.
25998834 Interleukin-17 and innate immunity in infections and chronic inflammation. 2015 Jun Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition.
27031443 Alarmin human α defensin HNP1 activates plasmacytoid dendritic cells by triggering NF-κB 2016 Jul Human neutrophil peptide 1 (HNP1), a predominant α defensin in the azurophilic granules of human neutrophils, is an alarmin capable of inducing the migration and maturation of human myeloid/conventional dendritic cells. However, it is not determined whether it can activate plasmacytoid dendritic cells (pDCs). Herein, we found that both human pDCs and CAL-1 cells, a pDC-like cell line, produced IFNα upon treatment with HNP1. Additionally, HNP1 could promote CpG ODN-induced pDC production of proinflammatory cytokines including IFNα. HNP1 triggered activation of NF-κB and nuclear translocation of interferon regulatory factor 1 (IRF1) in CAL-1 cells. HNP1 upregulation of cytokine expression in pDCs was inhibited by blockade of NF-κB activation or knockdown of IRF1, demonstrating the importance of these two signaling events in HNP1-induced pDC activation. Using a human pDC-nude mouse model, HNP1 was shown to induce IFNα production by human pDCs in vivo. Thus, HNP1 can activate human pDCs using NF-κB and IRF signaling pathways, and HNP-induced IFN production may participate in the inflammatory pathogenesis in certain authoimmune diseases such as rheumatoid arthritis.
26749327 Dual-Energy CT in Patients with Suspected Gouty Arthritis: Effects on Treatment Regimen an 2016 Mar RATIONALE AND OBJECTIVES: This investigation aimed to evaluate the impact on treatment regimen and clinical outcome of dual-energy computed tomography (DECT) in patients with suspected gouty arthritis. MATERIALS AND METHODS: We retrospectively analyzed electronic medical records (EMR) of 39 patients (36 male, 3 female; age range, 36-85 years) who underwent DECT of peripheral joints because of suspected gouty arthritis. We assessed the prior medical history, lab results, treatment regimen, and medications before and after DECT, and changes in subjective severity of symptoms as stated by patients in the EMR. The presence of monosodium urate (MSU) crystals in the index joint was verified with DECT. RESULTS: Several patients had a prior diagnosis of gout (n = 9), hyperuricemia (n = 6), rheumatoid arthritis (n = 3), or psoriatic arthritis (n = 3). Elevated uric acid blood levels were detected in 32 patients (82%) before DECT. On DECT, MSU crystals were detected in 23 patients (59%). Of the 36 cases, the current treatment regimen was modified after DECT to gout-specific therapy in 22 cases and other rheumatic diseases were targeted in 14 cases. Several medications were prescribed more frequently based after DECT compared to before DECT imaging, including steroids (n = 20 vs. n = 12, respectively), colchicine (n = 13 vs. n = 4, respectively), and urate-lowering medication (n = 18 vs. n = 11, respectively). A subjective reduction of clinical symptoms during cumulative follow-up was reported by 34 patients (87.2%). CONCLUSIONS: Both positive and negative findings of MSU crystals on DECT have a significant impact on the treatment regimen and clinical outcome of patients with suspected gouty arthritis and facilitate differentiation from other rheumatic diseases.
29429506 [What's new in internal medecine?]. 2016 Dec Answering the question « what's new in internal medecine in 2016? » is very challenging. We used 3 methods of article selection to reduce the selection bias: 3 authors, a systematic review of the articles discussed in the weekly bibliographic meeting of our unit (Dermatology department, Saint-Louis Hospital, Paris, France) and a selection of the best articles by several internal medecine practitioners in Paris. Eleven « hot topics » were analyzed: i/lowering cholesterol level but not blood blessure has a significant impact on cardiovascular morbi-mortality in cardiovascular intermediate risk patients; ii/the « treat to treat target » is efficient in psoriatic arthritis; iii/ a genotype/ phenotype correlation favors the separation of ileal Crohn's disease, colonic Crohn's disease and ulcerative colitis; iv/ tocilizumab treatment (anti-IL-6 monoclonal antibody ) is very efficient in giant cell arteritis and slightly efficient in systemic sclerosis; v/ combination therapy using methotrexate plus steroids compared with steroids alone becomes the « gold standard » treatment for juvenile dermatomyositis; vi/ dupilumab treatment (antibody blocking IL-4 and IL-13 receptors) is not only efficient in atopic dermatitis but also in asthma; vii/ think of eosinophilic oesophagitis in a patient with atopic dermatitis and dypshagia or food impaction; viii/ genetic A2 protein dysfunction induces NF-kB hyperactivation and an autoinflammatory disorder with features similar to Behcet's disease; ix/ no new biotherapies have shown high efficacy in systemic lupus erythematosus; x/ nanoparticles loaded with autoantigens induce Tregs and Bregs and may be a promising therapeutic option to treat auto-immune disease in the future; xi/ ipilimumab treatment (anti-CTLA4 antibody, immune checkpoint inhibitor) may induce complete remission in acute myeloid leukemia patients relapsing after haematological stem cell transplantation. Year 2016 is full of great discoveries in internal medicine keeping the dermatologist brain fully open minded.
26319019 Pyrroloquinoline Quinone Decelerates Rheumatoid Arthritis Progression by Inhibiting Inflam 2016 Feb Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient and antioxidant and has been reported to exert potent immunosuppressive effects. However, the therapeutically potential of PQQ on rheumatoid arthritis (RA) has not been explored. In the present study, the anti-inflammatory effects of PQQ were investigated in interleukin (IL)-1β-treated SW982 cells, a RA-like fibroblast-like synoviocytes (FLSs) injury model. Our observations showed that pretreatment with PQQ significantly inhibited the expression of matrix metalloproteinase (MMP)-1 and MMP-3 and suppressed the production of proinflammatory mediators such as TNF-α and IL-6 in IL-1β-treated SW982 cells. The nuclear translocation of nuclear factor kappa B (NF-κB) and the phosphorylation level of p65, p38, and JNK MAP kinase pathways were also inhibited by PQQ in IL-1β-stimulated SW982 cells. To further confirm the therapeutic effects of PQQ on RA in vivo, a collagen-induced arthritis (CIA) model was used. Mice treated with PQQ demonstrated marked attenuation of arthritic symptoms based on histopathology and clinical arthritis scores. These results collectively suggested that PQQ might be a promising therapeutic agent for alleviating the progress of RA.
26759164 Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patient 2016 Jan 13 BACKGROUND: Synovial infiltration of monocytes is commonly associated with inflammation in rheumatoid arthritis (RA). Toll-like receptors (TLRs) are innate sensors that recognize cell debris and microbial components in host, a process contributing to maintain chronic inflammation in RA. We assessed the expression levels of TLR2 and TLR9 in monocyte subsets of active RA patients and characterized their cytokine profiles in response to synthetic and viral TLR2 and TLR9 agonists, including Epstein-Barr virus (EBV) which is suspected to contribute to RA symptoms. METHODS: Prevalence of monocyte subsets CD14(++) CD16(-), CD14(+) CD16(+) and CD14(low) CD16(++) was evaluated in blood and synovial fluids of active RA patients and levels of TLR2 and TLR9 in monocyte subsets were measured by flow cytometry. Enriched monocytes derived from RA patients and healthy donors were stimulated in vitro with synthetic TLR2 and TLR9 agonists and with EBV particles or viral DNA. Intracellular cytokine profiles were determined in respective monocyte subsets. Finally, the presence of EBV genome was evaluated by real-time PCR in blood and synovial monocytes of RA patients. RESULTS: Numbers of CD14(+) CD16(+) and CD14(low) CD16(++) were found to increase in blood of RA patients compared to healthy controls, while all three subsets were detected in synovial fluids. TLR2 is abundantly expressed on blood and synovial CD14(++) CD16(-) and CD14(+) CD16(+) monocytes from RA patients. Levels of TLR9 were increased on all three subsets of blood monocytes but markedly enhanced in monocytes isolated from synovial fluids. Compared to healthy controls, CD14(++) CD16(-) monocytes of RA patients displayed an enlarged capacity to produce proinflammatory cytokines after stimulation with synthetic TLR2 and TLR9 agonists while both CD14(++) CD16(-) and CD14(+) CD16(+) monocytes showed increased response to EBV stimulation. The presence of EBV genome was also detected in monocytes and neutrophils of a significant proportion of patients. CONCLUSION: Patients with active RA show an increased expression of TLR2 and TLR9 on monocyte subsets and display higher production of inflammatory cytokines in response to TLR agonists. The presence of EBV genome in monocytes and neutrophils reinforces the suspected role of the virus in the exacerbation of RA symptoms.
26267000 Pain in primary Sjögren's syndrome. 2015 Feb Joint and muscle pain are commonly observed in patients with primary Sjögren's syndrome (pSS). Different types of pain can be distinguished, that is, articular pain, neuropathic pain and widespread pain. Articular pain is due to more or less evident synovitis, usually involving peripheral joints such as hand joints, wrists, knees and ankles. Drugs used to treat rheumatoid arthritis, or lupus synovitis, are also employed for articular involvement in pSS. Pure sensory neuropathies and, more often, small fibre neuropathies are responsible for neuropathic pain in pSS. This is usually localised in the legs and arms with a characteristic glove or sock distribution. Widespread pain, often assuming the features of fibromyalgia, has also been reported in patients with pSS. The pathological mechanisms underlying both neuropathic pain and widespread (fibromyalgia) pain in pSS have not been so far completely clarified.
26242127 [Effect of Combination Therapy of Tetramethylpyrazine with Methotrexate on Inflammatory Re 2015 Jun OBJECTIVE: To explore the effect of combination therapy of tetramethylpyrazine (TMP) with methotrexate (MTX) on collagen induced arthritis (CIA) rats. METHODS: Totally 55 male SD rats were stratified by body weight. Nine of them were randomly recruited as the normal control group. The rest 46 were immunized with type II bovine collagen (C II) for establishing rheumatoid arthritis (RA) model. Forty successfully modeled rats were randomly divided into 4 groups according to swollen toe degree, i.e., the CIA group, the TMP group, the MTX group, and the TMP plus MTX group, 10 in each group. Rats in the MTX group were administered with MTX (1. 2 mg/kg) , once per week for 4 continuous weeks. Those in the TMP group were administered with 40 mg/kg TMP, once per day for 10 continuous days, and then discontinued for 7 successive days, and continued for another 10 successive days. Rats in the TMP plus MTX group were administered with a mixture of equal dose MTX and TMP, and when MTX was discontinue, TMP was administered according to the way in the TMP group. Equal volume of saline solution was given to rats in the normal control group and the CIA group. Clinical parameters including ankle width (mediolateral diameter) and hindpaw swelling were measured at day 0, 4, 11, 18, and 26 after treatment. Rats were sacrificed 28 days after treatment, their knee joints and ankle joints were collected for pathological analyses. Serum levels of IL-1β, IL-6, and IL-17A were detected by ELISA. Changes of fibrinogen (FIB) and platelet aggregation rate (PAg) were detected. RESULTS: Compared with the normal control group, the ankle width and hindpaw swelling increased significantly (P < 0.01), contents of FIB and PAg increased obviously (P < 0.05, P < 0.01), serum levels of IL-1β, IL-6, and IL-17 increased remarkably (P <0. 01) in the CIA group. Obvious cell proliferation, inflammatory cell infiltration, hyperemia and edema of synovial tissues could be seen. Pannus formed and immerged in cartilages, resulting in necrosis. Compared with the model group, changes of ankle width and hindpaw swelling were all alleviated in each medicated group (P <0. 05, P <0. 01). Of them, the effect was superior in the MTX group to that of the TMP group and the MTX plus TMP group (P < 0.05, P < 0.01). Contents of FIB, serum levels of IL-1β and IL-6 decreased significantly in the MTX group (P < 0.05). Contents of FIB, serum levels of IL-1β and IL-6 decreased significantly in the TMP group and the MTX plus TMP group (P < 0.05). Besides, serum levels of FIB and IL-6 were obviously lower in the MTX plus TMP group than in the TMP group and the MTX group (P < 0.01). Levels of PAg and IL-17A were more significantly lowered in the TMP group than in the MTX plus TMP group and the MTX group. Pathological changes could be alleviated in each medicated group, with the optimal effect obtained in the MTX plus TMP group. CONCLUSION: Combination of TMP with MTX could significantly ameliorate inflammatory reactions and FIB contents of CIA rats.
25708025 Lubricin/Proteoglycan 4 Binding to CD44 Receptor: A Mechanism of the Suppression of Proinf 2015 Jun OBJECTIVE: To evaluate the binding of recombinant human proteoglycan 4 (rhPRG4) to CD44 receptor and its consequences on cytokine-induced synoviocyte proliferation. METHODS: The binding of rhPRG4 to CD44 and competition with high molecular weight (HMW) hyaluronic acid (HA) was evaluated using a direct enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance. Sialidase A and O-glycosidase digestion of rhPRG4 was performed, and CD44 binding was evaluated using ELISA. Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) were stimulated with interleukin-1β (IL-1β) or tumor necrosis factor α (TNFα) for 48 hours in the presence or absence of rhPRG4 or HMW HA at 20, 40, and 80 μg/ml, and cell proliferation was measured. The contribution of CD44 was assessed by coincubation with a CD44 antibody (IM7). The antiproliferative effect of rhPRG4 was investigated following treatment of PRG4(-/-) mouse synoviocytes with IL-1β or TNFα in the presence or absence of IM7. RESULTS: Recombinant human PRG4 bound CD44 and interfered with the binding of HMW HA to CD44. Removal of sialic acid and O-glycosylations significantly increased CD44 binding by rhPRG4 (P < 0.001). Both rhPRG4 and HMW HA at 40 and 80 μg/ml significantly suppressed IL-1β-induced proliferation of RA FLS (P < 0.05). Recombinant human PRG4 at 20, 40, and 80 μg/ml significantly suppressed TNFα-induced RA FLS proliferation (P < 0.05). CD44 neutralization reversed the effect of rhPRG4 on IL-1β- and TNFα-stimulated RA FLS and the effect of HMW HA on IL-1β-stimulated RA FLS. Recombinant human PRG4 inhibited cytokine-induced proliferation of PRG4(-/-) synoviocytes, which could be prevented by blocking CD44. CONCLUSION: PRG4 (lubricin) is a novel putative ligand for CD44 and may control synoviocyte overgrowth in inflammatory arthropathies via a CD44-mediated mechanism.
26350255 Naringenin inhibits dendritic cell maturation and has therapeutic effects in a murine mode 2015 Dec The aim of this study was to investigate the effect of naringenin (5,7,4'-trihydroxyflavanone), a citrus flavonoid, on dendritic cell (DC) maturation, as well as its potential as a therapeutic agent in a murine model of collagen-induced arthritis (CIA). Naringenin effectively inhibited lipopolysaccharide (LPS)-induced DC maturation as shown by reductions in the production of proinflammatory cytokines/chemokines, the expression of costimulatory molecules and the Ag-specific T cell priming ability of DCs when given at noncytotoxic doses. In addition, the decrease of LPS-induced MAPK and NF-κB signaling activation may contribute to the inhibitory activity of naringenin. In mice with CIA, the oral administration of naringenin ameliorated the severity of arthritis, reduced the levels of anticollagen Type II (CII) IgG and limited the proliferation of T cells, observed as a lower frequency of Th1 and Th17 cells in the spleen after restimulation with CII. In conclusion, this study shows for the first time that naringenin can manipulate the immunostimulatory properties of DCs and thus represents a potential therapeutic for the treatment of rheumatoid arthritis in humans.
27335194 [Sjögren's syndrome (SS), a review of the subject and saliva as a diagnostic method]. 2016 May Sjögren's syndrome is a chronic autoimmune disease whose main clinical manifestation is oral dryness (xerostomia) and ocular dryness (xerophthalmia). It is characterized by progressive mononuclear infiltration of the exocrine glands and can affect a variety of organ systems. The prevalence of primary Sjögren's syndrome varies from 0.01 up to 4.8%; this variability reflects differences in definition, application of diagnostic criteria, and geographic differences in age groups. The etiology of primary Sjögren's syndrome is unknown, but the interaction between genetic and environmental factors (viruses, hormones, vitamins, stress) is important. There are few reported cases of concordance in monozygotic twins, and it is common for patients with primary Sjögren's syndrome to have relatives with other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, thyroid disease, psoriasis, and multiple sclerosis. Among the most common findings is hypergammaglobulinemia. Elevated levels of γ-globulins contain autoantibodies directed against nonspecific antigens such as rheumatoid factor, antinuclear antibodies, and cellular antigens SS-A/Ro and SS-B/La. Regarding diagnosis, there have been 11 different published criteria for Sjögren's syndrome since 1965; none have been approved by the American College of Rheumatology or the European League Against Rheumatism. The current criteria were published in 2012 jointly with the progressive advance in the knowledge of the human salivary proteome that has gained wide acceptance in Sjögren's syndrome, with the possibility of using saliva as a useful tool in both diagnosis and prognosis in this field because the analysis of salivary proteins may reflect the state of locally underlying disease of the salivary glands, which are the target organs in this disease.
25495134 One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine 2015 Mar OBJECTIVE: To assess the long-term safety of the single-tablet combination of ibuprofen 800 mg and famotidine 26.6 mg. RESEARCH DESIGN AND METHODS: A phase 3b open-label study (NCT00984815) was conducted in 86 adults requiring daily non-steroidal anti-inflammatory drug (NSAID) administration for ≥12 months. The combination tablet of ibuprofen/famotidine was self-administered orally three times daily for up to 54 consecutive weeks. Adverse events (AEs) were collected beginning at the first dose and continued through completion (54 weeks). The Severity of Dyspepsia Assessment (SODA) questionnaire was completed by patients to assess tolerability. RESULTS: Most patients (65%) finished the trial, with 76% contributing data at 6 months, and 21% withdrew due to adverse effects. Overall and gastrointestinal AE discontinuation rates (21% and 13%, respectively) were lower than that previously reported with ibuprofen 2400 mg given alone. Each of the SODA subscale scores demonstrated improvement by week 6 and improved statistically significantly at week 24 and week 54. Of the cardiovascular AEs, hypertension was reported most frequently (9/86, 9.3%), with 3.5% determined to be drug related. Twelve serious AEs were reported by 9 of 86 (10%) patients; two were considered possibly related to the study medication (unstable angina and gastric ulcer). There were no reports of serious gastrointestinal or CV complications. Most AEs were mild or moderate in severity and not considered drug related. CONCLUSIONS: These data, together with previously reported findings of a significant decrease in upper gastrointestinal endoscopic ulcer rate at 6 months, support the overall safety, compliance, and tolerability of this single-tablet formulation.
25302624 Two dosing regimens of certolizumab pegol in patients with active rheumatoid arthritis. 2015 Feb OBJECTIVE: To investigate clinical efficacy and safety of 2 certolizumab pegol (CZP) maintenance dosing regimens plus methotrexate (MTX) in active rheumatoid arthritis (RA) patients achieving the American College of Rheumatology 20% improvement criteria (ACR20) after the CZP 200 mg every 2 weeks open-label run-in period. METHODS: DOSEFLEX (dosing flexibility) was a double-blind, placebo-controlled randomized study with an open-label run-in phase. During the run-in phase, all patients received CZP 400 mg (weeks 0, 2, and 4) and 200 mg every 2 weeks to week 16. Week 16 ACR20 responders were randomized 1:1:1 at week 18 to CZP 200 mg every 2 weeks, 400 mg every 4 weeks, or placebo. RESULTS: A total of 209 (of 333) patients were randomized at week 18 (CZP: 200 mg, n = 70; 400 mg, n = 70; placebo, n = 69). Groups had similar baseline characteristics (week 0). Week 34 ACR20 response rates were comparable between the CZP 200 mg every 2 weeks and the 400 mg every 4 weeks groups (67.1% versus 65.2%), which was significantly higher than placebo (44.9%; P = 0.009 and P = 0.017). ACR50/70 and remission criteria were met more frequently in CZP groups than placebo at week 34, with similar responses between anti-tumor necrosis factor-experienced and naive patients. Improvements from baseline Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and Health Assessment Questionnaire disability index scores were maintained in CZP groups from week 16 to 34 while worsening on placebo. Adverse event (AE) rates in the double-blind phase were 62.9% versus 60.9% versus 62.3%; serious AE rates were 7.1% versus 2.9% versus 0.0% (CZP 200 mg, 400 mg, and placebo groups). CONCLUSION: In active RA patients with an incomplete MTX response, CZP 200 mg every 2 weeks and 400 mg every 4 weeks were comparable and better than placebo for maintaining clinical response to week 4 following a 16-week, open-label run-in phase.
26212359 Proinflammatory receptor switch from Gαs to Gαi signaling by β-arrestin-mediated PDE4 r 2015 Nov OBJECTIVE: In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 inhibition was uneffective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/β-arrestin interaction at β-adrenoceptors resulted in switching from Gαs to Gαi signaling and ERK1/2 activation. Such a switch in signaling might elicit proinflammatory effects. We aimed to investigate this possible Gαs to Gαi signaling switch in RA and osteoarthritis (OA) mixed synoviocytes. METHODS: Synoviocytes were treated alone or with combinations of adrenergic, dopaminergic, and adenosinergic drugs, rolipram (PDE4 inhibitor), inhibitors of Gαi signaling (pertussis toxin), and blockers of protein kinase A (PKA). Under normoxic or hypoxic conditions, proinflammatory TNF was the readout-parameter. We investigated co-expression and interaction of PDE4 and β-arrestin by imaging techniques. Expression of pERK1/2 was analyzed by western blotting. RESULTS: Mixed synoviocytes in RA and OA possessed all major Gαs-coupled neurotransmitter receptors. Under hypoxia, particularly in RA cells, Gαs-coupled receptor agonists unexpectedly increased TNF and respective antagonists decreased TNF. Under hypoxia, rolipram alone or rolipram plus Gαs agonists increased TNF, which was reversed by pertussis toxin or PKA inhibition. Co-localization and interaction of PDE4 and β-arrestin in synovial tissue and cells was demonstrated. Gαs agonists or rolipram plus Gαs agonists increased pERK1/2 expression. CONCLUSIONS: This study in human arthritic synovial tissue presents an unexpected proinflammatory switch from Gαs to Gαi signaling, which depends on PDE4/β-arrestin interaction. This phenomenon is most probably responsible for reduced efficacy of PDE4 inhibitors and Gαs agonists in RA.
27639923 TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmun 2018 Jan TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNFα inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNFα causes its effects by binding to either or both of two membrane-bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNFα and depending on whether the cytokine is membrane-bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNFα and T cell signalling proteins can significantly impact the outcome of TNFα receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNFα. However, recent evidence indicates that the relationship between TNFα and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNFα on different T cell subsets. This review will summarise knowledge on how TNFα modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNFα inhibitors.