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ID PMID Title PublicationDate abstract
24471729 Calcium signaling and cell volume regulation are altered in Sjögren's Syndrome. 2014 Oct OBJECTIVE: Sjögren's Syndrome (SS) is a chronic autoimmune disease, leading to deficient secretion from salivary and lacrimal glands. Saliva production is normally increased by cholinergic innervation, giving rise to intracellular calcium signaling and water transport through water channels (aquaporins, AQPs). The aim of this study was to investigate possible pathophysiological changes in cell volume regulation, AQP expression and localization, and intracellular calcium signaling in glandular cells from SS patients compared to controls. MATERIALS AND METHODS: A total of 35 SS patients and 41 non-SS controls were included. Real time qPCR was combined with immunohistochemistry to analyze the mRNA expression and cellular distribution of AQP1, 3 and 5. Cell volume regulation and intracellular calcium signaling were examined in fresh acinar cells. RESULTS: We show for the first time a reduced mRNA expression of AQP1 and 5 in SS compared to controls, accompanied by a decrease in staining intensity of AQP1, 3 and 5 in areas adjacent to local lymphocytic infiltration. Furthermore, we observed that the SS cells' capacity for volume regulation was abnormal. Similarly, the calcium response after parasympathetic agonist (carbachol) stimulation was markedly decreased in SS cells. CONCLUSIONS: It is concluded that mRNA expression of AQP1 and 5, protein distribution of AQP1, 3 and 5, glandular cell volume regulation and intracellular calcium signaling are all altered in SS, pointing to possible pathophysiological mechanisms in SS.
24018503 Hepatocellular carcinoma that arose from primary Sjögren's syndrome. 2013 Sep Hepatocellular carcinoma (HCC) typically originates from HBV or HCV associated liver cirrhosis. Primary Sjögren's syndrome (pSS) is a kind of autoimmune disease. A sixty-two year old female patient with mild liver damage was diagnosed with pSS after excluding viral, alcoholic and drug-induced hepatitis according to serum immunological detection and liver biopsy. But when she was hospitalized for a second time two years later, a CT scan revealed liver neoplasm. Surgery confirmed HCC and liver cirrhosis by pathology. The elevated level of AFP recovered to normal after tumorectomy. In conclusion, HCC might be a candidate outcome in patients with pSS; it is the doctors' responsibility to keep this kind of patient under surveillance.
23727029 Clinical performance evaluation of a novel rapid response chemiluminescent immunoassay for 2013 Sep 23 BACKGROUND: We analyzed the performance of a novel ENA screening chemiluminescent immunoassay (CIA) and the confirmation QUANTA Flash tests. METHODS: Sera (n=1079) from patients referred to a rheumatology clinic were screened by QUANTA Flash ENA7 (INOVA Diagnostics). All positive (n=89) and a matched control group (n=90) were reflexed for autoantibodies to the individual antigens. Moreover, sera from patients with systemic lupus erythematosus (SLE, n=252), systemic sclerosis (SSc, n=64), polymyositis/dermatomyositis (PM/DM, n=72), Sjögren's syndrome (SjS, n=39) as well as disease controls (n=605) were tested by ENA7 CIA and by Quanta Lite ENA6 ELISA (INOVA). RESULTS: 89/1079 (8.3%) samples were ENA7 CIA positive with the following reactivity profile: RNP (36.0%), Sm (13.5%), Scl-70 (9.0%), Jo-1 (0.0%), Ro60 (44.9%), Ro52 (39.3%) and SS-B (24.7%). In the negative group, the reactivity profile was: RNP (1.1%), Sm (1.1%), Scl-70 (2.2%) and 0.0% for Jo-1, Ro60, Ro52 and SS-B. The positive/negative/total agreements (ENA7 CIA vs. confirmation assays) were 95.3%/91.5%/93.3%. The sensitivity of the ENA7 CIA was 62.3% in SLE, 54.7% in SSc, 92.3% in SjS, 50.0% in PM/DM, and 61.8% in the total systemic autoimmune rheumatic disease (SARD) population (specificity 95.0%). CONCLUSION: The QUANTA Flash ENA7 CIA is a reliable screening test.
25056402 Frequent involvement of central nervous system in primary Sjögren syndrome. 2015 Feb Primary Sjögren syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the salivary and tear glands, and autoantibody secretion, in the absence of other systemic autoimmune disorder. Among autoimmune diseases, it is a relatively common disease, but the burden of central nervous system (CNS) involvement is controversial. This retrospective study evaluates the prevalence, clinical patterns and outcomes of CNS involvement in a cohort of patients with primary Sjögren syndrome. We evaluated 93 patients with pSS diagnosed according to American-European Consensus Group criteria. Fourteen patients (15.1 %) had CNS involvement. All were women with an average age of onset of the disease of 42.1 ± 14.7 years (average ± SD) and an average age of onset of neurological involvement of 47.29 ± 16 years. Three had parkinsonian syndrome, two epilepsy, two motor and sensory deficits, two headache with brain magnetic resonance abnormalities, two neuromyelitis optica, two chronic progressive myelitis and one aseptic meningitis. Neurological involvement preceded Sjögren syndrome diagnosis in nine of the patients (64 %), and neurological outcome was good in 11 patients (78.6 %). Central nervous involvement was not as rare as expected, and the frequency was similar to the frequency of peripheral nervous system involvement. In half of the patients, this was the first symptom of the disease, emphasizing the importance of considering this diagnosis, especially in young female with neurological symptoms without other evident cause.
23975864 Expression of the immune regulator tripartite-motif 21 is controlled by IFN regulatory fac 2013 Oct 1 Tripartite-motif 21 (TRIM21) is an E3 ubiquitin ligase that regulates innate immune responses by ubiquitinating IFN regulatory factors (IRFs). TRIM21 is mainly found in hematopoietic cells in which its expression is induced by IFNs during viral. infections and in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome. However, the exact molecular mechanism by which the expression of the Trim21 gene is regulated is unknown. In this study, we demonstrate that IFNs induce Trim21 expression in immune cells via IRFs and that IFN-α and IFN-β are the most potent inducers of Trim21. A functional IFN-stimulated response element but no conserved IFN-γ-activated site was detected in the promoter of Trim21. IRF1 and IRF2 strongly induced Trim21 expression in an IFN-stimulated response element-dependent manner, whereas IRF4 and IRF8 strongly repressed the IRF1-mediated induction of Trim21. Consistent with this observation, baseline expression of Trim21 was elevated in Irf4(-/-) cells. TRIM21, IRF1, and IRF2 expression was increased in PBMCs from patients with Sjögren's syndrome compared with healthy controls. In contrast, IRF4 and IRF8 expression was not increased in PBMCs from patients. The IFN-γ-mediated induction of Trim21 was completely abolished by inhibiting protein synthesis with cycloheximide, and Trim21 expression could not be induced by IFN-γ in Irf1(-/-) cells, demonstrating that IFN-γ induces Trim21 indirectly via IRF1 and not directly via STAT1 activation. Our data demonstrate that multiple IRFs tightly regulate expression of Trim21 in immune cells, suggesting that a well-controlled expression of the E3 ligase TRIM21 is important for regulation of immune responses.
23906036 The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response 2013 Nov OBJECTIVE: Innate and adaptive immunity may contribute to gland dysfunction in patients with primary Sjögren's syndrome (pSS). The P2X7 receptor (P2X7 R)-NLRP3 inflammasome complex modulates the release of the inflammatory cytokines IL-1β and IL-18. The presence of P2X7 R in salivary glands suggests an interesting scenario for the initiation and amplification of the innate immune response in pSS. Therefore, the aim of this study was to assess the role of the P2X7 R-NLRP3 inflammasome in pSS. SUBJECTS AND METHODS: Twenty-one consecutive patients with pSS according to the American-European Consensus Group criteria and 15 patients with sicca syndrome (i.e. without Sjögren's syndrome, non-SS) were enrolled in this study, together with six control (CTL) subjects. Expression of the P2X7R-NLRP3 platform and IL-18 was determined by real-time PCR and western blotting in gland specimens and peripheral lymphomonocytes; data were related to patientsx92 clinical, serological and histopathological characteristics. The presence of IL-18 was determined in gland and saliva samples. RESULTS: P2X7 R expression was significantly higher in salivary glands from individuals with pSS than in those from non-SS and CTL subjects. Accordingly, the gene expression levels of the inflammasome components NLRP3, ASC and caspase-1 were significantly higher in pSS gland specimens, and this was paralleled by an increased expression of mature IL-18 in pSS saliva samples. The expression of both the P2X7 R and the inflammasome components was a marker of disease-related glandular involvement, being increased in patients with anti-Ro/SSA positivity and correlated with focus score. CONCLUSION: The results of this study suggest an involvement of the P2X7 R-inflammasome-caspase-1-IL-18 axis in the development of pSS exocrinopathy. This finding provides the basis for studying the complex mechanisms underlying pSS, as well as for developing novel potential therapeutic strategies.
23622253 Association of TNFSF4 polymorphisms with susceptibility to primary Sjögren's syndrome and 2013 Jul OBJECTIVES: We aimed to evaluate the association between polymorphisms of TNFSF4 and primary Sjögren's syndrome (pSS) and primary biliary cirrhosis (PBC) in a Chinese Han population. METHODS: A total of 250 pSS patients, 221 PBC patients, and 393 healthy controls were enrolled. All individuals were ethnic Chinese Han, and each group was matched for gender ratio and age. We identified single nucleotide polymorphisms (SNPs) via the HapMap Han Chinese Beijing databank for a genetic region containing TNFSF4, and then identified haplotype tagging SNPs with the Tagger programme of Haploview. DNA samples were amplified through polymerase chain reaction (PCR) and extension products were differentiated via mass spectrometry. Association analyses were performed using PLINK software. RESULTS: In TNFSF4, T allele and TT genotype of rs2205960, and G allele of rs1234313, were associated with pSS (p<0.05); T allele of rs2205960 was correlated with PBC (p<0.05) as a risk factor. In the haplotype analysis, TAGG and TGGT were correlated with pSS (p<0.05). In genetic additive, dominant, and recessive models analysis, rs2205960 had a significant association with both pSS and PBC, and rs1234313 presented a significant association with pSS (p<0.05). However, no statistically significant difference was found after Bonferroni corrections. CONCLUSIONS: Overall, no association between the allele, or genotype, or haplotype frequencies of TNFSF4 and the risk of pSS or PBC was found. TNFSF4 may have little significance as a common genetic component of pSS and PBC in the Chinese Han population.
23334994 Rituximab therapy for primary Sjögren's syndrome: an open-label clinical trial and mechan 2013 Apr OBJECTIVE: To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms. METHODS: Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression. RESULTS: Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature. CONCLUSION: In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.
25253552 Protective Effect of Zengye Decoction () on Submandibular Glands in Nonobese Diabetic Mice 2019 Jan OBJECTIVE: To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice. METHODS: Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction. RESULTS: Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05). CONCLUSIONS: ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.
25433020 Systemic activity and mortality in primary Sjögren syndrome: predicting survival using th 2016 Feb OBJECTIVE: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS). PATIENTS AND METHODS: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. RESULTS: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. CONCLUSIONS: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.
23307206 Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for 2013 Jan OBJECTIVES: To determine the clinical sensitivity, specificity, negative predictive value, and positive predictive value of a rapid point-of-care diagnostic test to detect elevated matrix metalloproteinase 9 levels (InflammaDry). METHODS: In a prospective, sequential, masked, multicenter clinical trial, InflammaDry was performed on 206 patients: 143 patients with clinical signs and symptoms of dysfunctional tear syndrome (dry eyes) and 63 healthy individuals serving as controls. Participants were assessed as healthy controls or for a clinical diagnosis of dry eye using the Ocular Surface Disease Index, Schirmer tear test, tear breakup time, and keratoconjunctival staining. MAIN OUTCOME MEASURES: The sensitivity and specificity of InflammaDry were compared with clinical assessment. RESULTS: InflammaDry showed sensitivity of 85% (in 121 of 143 patients), specificity of 94% (59 of 63), negative predictive value of 73% (59 of 81), and positive predictive value of 97% (121 of 125). CONCLUSION: Compared with clinical assessment, InflammaDry is sensitive and specific in diagnosing dry eye. APPLICATION TO CLINICAL PRACTICE: Dry eye is often underdiagnosed resulting from poor communication between the clinical assessment of dry eye severity between clinicians and patients. This often leads to a lack of effective treatment. Matrix metalloproteinase 9 is an inflammatory biomarker that has been shown to be elevated in the tears of patients with dry eyes. The ability to accurately detect elevated matrix metalloproteinase 9 levels may lead to earlier diagnosis, more appropriate treatment, and better management of ocular surface disease. Preoperative and perioperative management of inflammation related to dry eyes may reduce dry eyes that develop after laser in situ keratomileusis, improve wound healing, and reduce flap complications. Recognition of inflammation may allow for targeted perioperative therapeutic management of care for patients who undergo cataract and refractive surgery and improve outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01313351.
23055441 Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated dise 2013 Jan OBJECTIVE: To compare the incidence of cancer following tumor necrosis factor α (TNFα) inhibitor therapy to that with commonly used alternative therapies across multiple immune-mediated diseases. METHODS: The Safety Assessment of Biological Therapeutics study used data from 4 sources: national Medicaid and Medicare databases, Tennessee Medicaid, pharmacy benefits plans for Medicare beneficiaries in New Jersey and Pennsylvania, and Kaiser Permanente Northern California. Propensity score-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were computed to estimate the relative rates of cancer, comparing those treated with TNFα inhibitors to those treated with alternative disease-modifying therapies. The cancer-finding algorithm had a positive predictive value ranging from 31% for any leukemia to 89% for female breast cancer. RESULTS: We included 29,555 patients with rheumatoid arthritis (RA) (13,102 person-years), 6,357 patients with inflammatory bowel disease (1,508 person-years), 1,298 patients with psoriasis (371 person-years), and 2,498 patients with psoriatic arthritis (618 person-years). The incidence of any solid cancer was not elevated in RA (HR 0.80 [95% CI 0.59-1.08]), inflammatory bowel disease (HR 1.42 [95% CI 0.47-4.26]), psoriasis (HR 0.58 [95% CI 0.10-3.31]), or psoriatic arthritis (HR 0.74 [95% CI 0.20-2.76]) during TNFα inhibitor therapy compared to disease-specific alternative therapy. Among RA patients, the incidence of any of the 10 most common cancers in the US and of nonmelanoma skin cancer was not increased with TNFα inhibitor therapy compared to treatment with comparator drugs. CONCLUSION: Short-term cancer risk was not elevated among patients treated with TNFα inhibitor therapy relative to commonly used therapies for immune- mediated chronic inflammatory diseases in this study.
25179851 Comprehensive arthritis referral study -- phase 2: analysis of the comprehensive arthritis 2014 Oct OBJECTIVE: Rheumatologists triage referrals to assess those patients who may benefit from early intervention. We describe a referral tool and formally evaluate its sensitivity for urgent and early inflammatory arthritis (EIA) referrals. METHODS: All referrals received on a standardized referral tool were reviewed by a rheumatologist and, based on the information conferred, assigned a triage grade using a previously described triage system. Each referral was also dichotomized as suspected EIA or not. After the initial rheumatologic assessment, the diagnosis was recorded and a consultation grade, blinded to referral grade, was assigned to each case. Agreement between referral and consultation grades was assessed. A regression analysis was performed to determine factors that predicted truly urgent referrals including EIA. RESULTS: We evaluated 696 referrals. A total of 210 (30.2%) were categorized as urgent at the time of consultation. The referral tool was able to successfully detect 169 of these referrals (sensitivity 80.5%, specificity 79.4%). EIA occurred in 95 (13.6%); of those referrals, 86 were correctly classified as urgent at the time of triage (sensitivity 90.5%, specificity 69.6%). Items that helped correctly discriminate urgent or EIA referrals included patient age < 60, duration of disease, morning stiffness, patient-reported joint swelling, a personal or family history of psoriasis, urgency as rated by referring physician, prior assessment by a rheumatologist, elevated C-reactive protein, and a positive rheumatoid factor. CONCLUSION: A 1-page referral tool that includes parts completed by the referring physician and patient has good sensitivity to detect urgent referrals including EIA.
23295110 Certolizumab pegol attenuates the pro-inflammatory state in endothelial cells in a manner 2013 Mar OBJECTIVES: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and premature cardiovascular death. Anti-TNF therapy is thought to reduce clinical cardiovascular disease risk and improve vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to explore the effects of certolizumab pegol (CZP) on TNF-activated human aortic endothelial cells (HAoECs). METHODS: HAoECs were cultured in vitro and exposed to i) TNF alone, ii) TNF plus CZP, or iii) neither agent. Microarray analysis and quantitative polymerase chain reaction were used to analyse gene expression. Activation of NF-κB was investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was performed to detect microparticle release from HAoECs. RESULTS: TNF alone had strong effects on endothelial gene expression, while TNF and CZP together produced a global gene expression pattern similar to untreated controls. In particular, genes for E-selectin, VCAM-1 and ICAM-1 were significantly up-regulated by TNF treatment. Notably, the TNF/CZP cocktail prevented the up-regulation of these genes. TNF-induced nuclear translocation of NF-κB was abolished by treatment with CZP. In addition the increased production of endothelial microparticles in TNF-activated HAoECs was prevented by treatment with CZP. CONCLUSIONS: We have found at cellular level, that a clinically available TNF inhibitor, CZP i) reduces adhesion molecule expression; ii) prevents TNF-induced activation of the NF-κB pathway and iii) prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions.
24713140 Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor 2014 Jun Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile.
25580314 Polyangiitis with granulomatosis as a paraneoplastic syndrome of B-cell lymphoma of the la 2014 Introduction. The clinical course of an autoimmune paraneoplastic syndrome parallels the natural history of the primary malignancy. In most cases, such paraneoplastic are syndromes hardly distinguishable from idiopathic autoimmune diseases. A case of polyangiitis with granulomatosis as a paraneoplastic syndrome in a patient with B-cell Lymphoma of the lacrimal gland has not yet been reported. Case Presentation. We present the case of a male patient with a B-cell Lymphoma of the lacrimal gland, who debuted with symptoms similar to rheumatoid arthritis and acute renal failure, secondary to polyangiitis with granulomatosis. The current pathophysiological hypotheses explaining the relationship between a lymphoproliferative disease and an autoimmune paraneoplastic disorder are discussed. Conclusion. Tumor-associated segmental necrotizing glomerulopathy is a very rare manifestation of glomerular diseases. Some atypical clinical features should increase the suspicion of an underlying tumor, in which case it is essential to treat the primary neoplasia, in order to control the autoimmune manifestations.
25227303 IBD therapy: new targets and unmet needs. 2014 Inflammatory bowel diseases (IBD) are chronic progressive diseases. Current therapeutic strategies have not significantly altered the natural history of IBD. In the wake of other chronic diseases, such as rheumatoid arthritis, the goal of therapy has now shifted from mere control of symptoms to altering natural history to prevent bowel damage and disability. A 'treat to target' approach using endoscopic healing as a first definition of the target is now proposed together with tight control of inflammation based on monitoring of symptoms and biomarkers. In order to reach the target, optimization of current therapies using better understanding of pharmacokinetics is needed as well as development of predictors of disease progression to avoid under- and overtreating. Advances in the understanding of the roles of the adaptive and innate immune systems, as well as the intestinal epithelium and endothelium have resulted in the development of multiple new biologics. There is great optimism that an integrated 'omics' approach incorporating genetic, microbiota with clinical and environmental data will help in choosing for each patient a personalized approach targeting the mechanisms driving the disease. Finally, in this era of increasing complexity of care, education of patients to involve them in a well-informed decision-making process is mandatory.
25149974 Phenylbutazone and ketoprofen binding to serum albumin. Fluorescence study. 2014 Oct BACKGROUND: A combination of phenylbutazone (PBZ) and ketoprofen (KP) is popular in therapy of rheumatoid arthritis (RA) but could be unsafe due to the uncontrolled growth of toxicity. METHODS: Quenching fluorescence of serum albumin in the presence of the both drugs has been characterized by dynamic KQ [M(-1)], static V [M(-1)] quenching constants and also association constants Ka [M(-1)]. RESULTS: The quenching of tryptophanyl residues fluorescence by the KP and PBZ indicates the capability of these drugs to accept the energy from Trp-214 and Trp-135. Strong displacement of KP and PBZ bound to albumin cause by the binding of the second drug to SA close to Trp-214 (subdomain IIA) has been obtained. The displacement was also confirmed on the basis of quenching and association constants. CONCLUSIONS: The conclusion, that both PBZ and KP form a binding site in the same subdomains (IIA or/and IB), points to the necessity of using a monitoring therapy owning to the possible increase of the uncontrolled toxic effects.
25071589 Vitamin D in inflammatory diseases. 2014 Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.
24868498 The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. 2013 Dec 1 Crohn's disease (CD) and ulcerative colitis (UC), collectively called inflammatory bowel disease (IBD), are immune-mediated conditions characterized by a chronic inflammation of the gut. Their precise etiology is unknown, although an increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD. The intestinal epithelium provides the largest interface between the external environment and the host, and is thus a crucial regulation site of innate and adaptive immunity. Zonulin is one of the few known physiological mediators of paracellular intestinal permeability. It was found upregulated in different immune diseases like Celiac disease and Type 1 Diabetes (T1D). Recently, human zonulin was identified as prehaptoglobin-2 (pre-HP2) which before only had been regarded as the inactive precursor for HP2. Haptoglobin (HP) is a hemoglobin-binding protein with immunomodulatory properties. Its gene harbors a common polymorphism with 2 different alleles: HP1 and HP2. Allele HP2 and genotype HP22 has been shown to be overrepresented in different immune diseases like Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and T1D, and has also been found to be more frequent in patients with IBD (UC and CD) than in healthy controls.   In order to get some clues about the mechanism of action of HP(2) in IBD pathogenesis, we here review the current state of knowledge about zonulin and haptoglobin structure and function, and their plausible role in immune mediated diseases with an emphasis on IBD.