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ID PMID Title PublicationDate abstract
25496409 Pulmonary infections following immunosuppressive treatments during hospitalization worsen 2015 Jul OBJECTIVE: Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP. METHODS: A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model. RESULTS: A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates. CONCLUSION: Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.
25465161 2-Methoxyestradiol inhibits bleomycin-induced systemic sclerosis through suppression of fi 2015 Jan BACKGROUND: The most dominant feature of systemic sclerosis (SSc) is fibrosis, which is caused by overproduction of collagen by fibroblasts. 2-Methoxyestradiol (2-ME) has exhibited disease-modifying activity in animal models of rheumatoid arthritis and autoimmune encephalomyelitis and inhibitory effect in cell proliferation and collagen synthesis. Therefore, we hypothesized that 2-ME may exhibit antifibrotic effect in SSc. OBJECTIVE: To investigate the antifibrotic effect of 2-ME in SSc. METHODS: We established a bleomycin-induced SSc mice model by injection with bleomycin daily for 21 days. 2-ME (100mg/kg/d) was simultaneously administered for 14 days. On the end of Week1 (W1), W2, W3 and W4, skins and lungs were collected for histological examination and analysis of hydroxyproline content and mRNA level of α1(I) procollagen (COL1A1) and COL1A2. In skin fibroblasts derived from SSc patients and healthy subjects treated with 2-ME (1, 5, or 25 μM), we examined cell proliferation, expression of α-smooth muscle actin (SMA) and mRNA level of COL1A1, COL1A2, COL3A1, matrix metalloproteinase(MMP)-1 and tissue inhibitors of MMP (TIMP)-1. RESULTS: We found reduced dermal thickness and lung fibrosis and decreased hydroxyproline content and mRNA level of COL1A1 and COL1A2 in skin and lung in SSc mice treated with 2-ME. In cell study, we observed a dose- and time-dependent inhibitory effect on proliferation of SSc fibroblasts by 2-ME. We also detected reduced α-SMA expression, decreased mRNA level of COL1A1, COL1A2, COL3A1 and TIMP-1, and increased mRNA level of MMP-1 in SSc fibroblasts treated with 2-ME. CONCLUSION: 2-ME could suppress SSc tissue fibrosis, which may be attributable to its inhibitory effect on the excessive proliferation, differentiation and production of collagen in fibroblasts. 2-ME is rising as a prospective agent for control of fibrosis in SSc.
25354407 Treatment of forefoot problems in older people: a randomized clinical trial comparing podi 2014 Sep PURPOSE: Consultations for forefoot pain are frequent in primary care, but scientific support of treatment options is scarce. The purpose of this study is to investigate the effect of podiatric treatment vs standardized advice on proper shoe characteristics and fit of shoes by means of an information leaflet for people aged 50 years and older with forefoot pain in primary care. METHODS: In this randomized controlled trial, 205 participants aged 50 years and older with hindering nontraumatic forefoot pain have been recruited at their general practitioner's office. Exclusion criteria were treatment of forefoot problem of less than 6 months' duration before inclusion, rheumatoid arthritis, and diabetic neuropathy or having pain considered not to be musculoskeletal (eg, warts). Participants received shoe advice by means of an information leaflet or podiatric care. Foot pain, foot-related dysfunction, general health, and social participation were assessed by means of questionnaires every 3 months for 1 year. Using multilevel analysis, we analyzed results at the level of (1) outcome measures, (2) the individual, and (3) the general practitioner. RESULTS: No differences were found between the 2 treatment groups. Both intervention groups showed an improvement over time in foot pain and foot-related dysfunction. CONCLUSION: This study found that shoe advice provided to patients consulting their general practitioner for forefoot pain and symptom relief resulted in outcomes similar to treatment outcomes in patients consulting a podiatrist. Based on these results, primary care physicians should be cautious when referring a patient to a podiatrist; instead, they should start by providing advice on proper characteristics and fit of shoes.
25303416 Prospective analysis of rural-urban differences in demographic patterns and outcomes follo 2014 Oct OBJECTIVE: Little is known about whether rural-urban differences exist in patients after hip and knee joint replacement surgery. We compared patient characteristics, pain and functional outcomes of rural and urban patients undergoing joint replacement surgery in a single high-volume metropolitan centre. DESIGN: Prospective cohort study conducted in patients who underwent primary elective hip (THJR) or knee replacement (TKJR) between 1 January 2006 and 31 December 2009. SETTING: A university-affiliated tertiary referral centre situated in the central metropolitan region of Melbourne, Australia. PARTICIPANTS: One thousand nine hundred fifty-five consecutive patients undergoing primary total joint replacement. MAIN OUTCOME MEASURE: Pain and function were assessed preoperatively and 12 and 24 months postoperatively. The main independent variable was geographic location specifically comparing patients residing in rural/regional compared with urban communities. RESULTS: A total of 2193 primary joint replacements were performed (981 THJR and 1212 TKJR) in 1955 patients. Rural patients presented at a younger age and with earlier radiographic disease than their urban counterparts. There was a higher rate of rheumatoid arthritis among rural patients presenting for TKJR. There was no difference in pain and function scores between groups at 12 and 24 months post-surgery. CONCLUSION: In our series of 1955 patients undergoing total hip and knee joint replacement surgery, rural patients presented at a younger age and an earlier stage of disease progression. At 24 months, rural patients had pain and functional outcomes as good as their urban counterparts. More research is required to determine which factors lead to the early presentation of rural patients.
26401361 Proximate composition, mineral content and in vitro antioxidant activity of leaf and stem 2014 Jul AIM: This study was designed to determine the proximate composition and mineral content of Costus afer leaf and stem, as well as to identify the most active antioxidant fraction. MATERIALS AND METHODS: The proximate composition and mineral analysis of C. afer leaf and stem were performed using the standard methods described by Pearson and Association of Official Analytical Chemist while the 1,1 diphenyl 2 picryl hydrazyl (DPPH), thiobarbituric acid reactive species (TBARS), lipid peroxidation (LPO), and total antioxidant capacity (TAC) assays were used to determine the in vitro antioxidant activity of aqueous, n-butanol, ethyl acetate and hexane fractions of C. afer leaf and stem. RESULTS: Proximate analysis revealed that the carbohydrate content was highest in the leaf (55.83 ± 3.71%) and stem (50.38 ± 1.27%) while crude fat content was lowest in the leaf (1.83 ± 0.43%) and stem (1.75 ± 0.48%). The minerals detected in appreciable quantity in both the leaf and stem samples were calcium, magnesium, potassium, sodium, chromium, lead, manganese, nickel, and copper. Further study showed that the aqueous leaf fraction exhibited a significantly (P < 0.05) high DPPH scavenging activity (IC50 = 259.07 µg/ml) and TAC (7.95 ± 0.37 mg ascorbic acid equivalent/g) compared with the other test fractions while the aqueous stem fraction had the highest TBARS scavenging activity (IC50 = 0.37 µg/ml) and inhibition of LPO (IC50 = 41.15 µg/ml) compared with the other test fractions. CONCLUSION: The findings from this study indicate that C. afer could serve as a source of nutrient and minerals for animal nutrition and human metabolism. It also showed that the aqueous fractions of C. afer leaf and stem possess high antioxidant activity than the other fractions. In addition, this study may also explain the folkloric use of crude C. afer leaf or stem extracts in the treatment of oxidative stress associated diseases, including rheumatoid arthritis and hepatic disorder.
24903731 Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity. 2014 Oct Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid-eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren's syndrome were 'protective' for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO.
24840767 Do inpatient multidisciplinary rehabilitation programmes improve health status in people w 2014 Dec BACKGROUND: Long-term musculoskeletal (MSK) conditions impair health and function. Guidelines recommend a multidisciplinary team (MDT) approach for the optimum management of people with long-term MSK conditions, but there is limited evidence for MDT care. This service evaluation investigates the short-term effectiveness of an inpatient MDT rehabilitation programme on self-reported function and disease status in people with long-term MSK conditions. METHODS: A convenience sample of adults with rheumatoid arthritis (RA), osteoarthritis (OA), low back pain (LBP) and chronic widespread pain (CWP) participated in an inpatient MDT rehabilitation programme, consisting of needs assessment, collaborative goal setting and planning, exercise and self-management. The Routine Assessment of Patient Index Data (RAPID3) (primary outcome), the Multi-Dimensional Health Assessment Questionnaire (MDHAQ), Pain Visual Analogue Scale (VAS) and global well-being VAS were assessed at baseline and immediately following MDT rehabilitation. RESULTS: A total of 183 people [mean age 62 (standard deviation, 14.5) years, 145 females] with RA, OA, LBP or CWP were evaluated before and after inpatient MDT rehabilitation (median duration, ten days). Overall, there was a 28% improvement in RAPID3 (mean difference [95% confidence intervals] in effect size, 5.0 [4.3, 5.8], d=-0.98, p<0.05). Clinically relevant changes were found in people with RA (5.7 [4.4, 6.9], d=-1.08, p<0.05, 32%), OA 6.1 [3.4, 8.7], d=-1.07, p<0.05, 35%), LBP 4.0 [2.8, 5.2], d=-0.91, p<0.05, 22%), CWP 4.6 [2.7, 6.6], d=-0.84, p<0.05, 25%). These changes were reflected in all secondary outcomes. CONCLUSION: This inpatient MDT rehabilitation programme provides short-term evidence of improved function and disease status in people with long term MSK conditions.
24782596 Polymorphisms in the tumor necrosis factor receptor genes affect the expression levels of 2014 The level of TNF receptors on various cells of immune system and its association with the gene polymorphism were investigated. Determining the levels of membrane-bound TNFα receptors on peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry using BD QuantiBRITE calibration particles. Soluble TNF α receptor (sTNFRs) levels were determined by ELISA and genotyping was determined by PCR-RFLP. Homozygous TT individuals at SNP -609G/T TNFRI (rs4149570) showed lower levels of sTNFRI compared to GG genotype carriers. Homozygous carriers of CC genotype at SNP -1207G/C TNFRI (rs4149569) had lower expression densities of membrane-bound TNFRI on intact CD14(+) monocytes compared to individuals with the GC genotype. The frequency differences in the CD3(+) and CD19(+) cells expressing TNFRII in relation to SNP -1709A/T TNFRII (rs652625) in healthy individuals were also determined. The genotype CC in SNP -3609C/T TNFRII (rs590368) was associated with a lower percentage of CD14(+) cells expressing TNFRII compared to individuals with the CT genotype. Patients with rheumatoid arthritis had no significant changes in the frequencies of genotypes. Reduced frequency was identified for the combination TNFRI -609GT + TNFRII -3609CC only. The polymorphisms in genes represent one of cell type-specific mechanisms affecting the expression levels of membrane-bound TNF α receptors and TNF α -mediated signaling.
24741573 Interpretation of ANA indirect immunofluorescence test outside the darkroom using NOVA vie 2014 OBJECTIVE: To evaluate NOVA View with focus on reading archived images versus microscope based manual interpretation of ANA HEp-2 slides by an experienced, certified medical technologist. METHODS: 369 well defined sera from: 44 rheumatoid arthritis, 50 systemic lupus erythematosus, 35 scleroderma, 19 Sjögren's syndrome, and 10 polymyositis patients as well as 99 healthy controls were examined. In addition, 12 defined sera from the Centers for Disease Control and 100 random patient sera sent to ARUP Laboratories for ANA HEp-2 IIF testing were included. Samples were read using the archived images on NOVA View and compared to results obtained from manual reading. RESULTS: At a 1 : 40/1 : 80 dilution the resulting comparison demonstrated 94.8%/92.9% positive, 97.4%/97.4% negative, and 96.5%/96.2% total agreements between manual IIF and NOVA View archived images. Agreement of identifiable patterns between methods was 97%, with PCNA and mixed patterns undetermined. CONCLUSION: Excellent agreements were obtained between reading archived images on NOVA View and manually on a fluorescent microscope. In addition, workflow benefits were observed which need to be analyzed in future studies.
24445038 Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a r 2014 Feb Curcumin is a phytocompound found in the root of turmeric, a common herbal ingredient in many Asian cuisines. The compound contains anti-inflammatory activity, which is mediated through an up-regulation of adiponectin and reduction of leptin. Consumption of curcumin was shown to prevent some deteriorative conditions caused by inflammation, such as ulcerative colitis, rheumatoid arthritis and esophagitis, and so on. Inflammation-associated cardiovascular conditions such as atherosclerosis are common in diabetes patients. The anti-inflammation effect of curcumin might be beneficial to prevent such condition in these patients. We aim to evaluate an antiatherosclerosis effect of curcumin in diabetes patients. Effects of curcumin on risk factors for atherosclerosis were investigated in a 6-month randomized, double-blinded and placebo-controlled clinical trial that included subjects diagnosed with type 2 diabetes. An atherosclerosis parameter, the pulse wave velocity, and other metabolic parameters in patients treated with placebo and curcumin were compared. Our results showed that curcumin intervention significantly reduced pulse wave velocity, increased level of serum adiponectin and decreased level of leptin. These results are associated with reduced levels of homeostasis model assessment-insulin resistance, triglyceride, uric acid, visceral fat and total body fat. In summary, a 6-month curcumin intervention in type 2 diabetic population lowered the atherogenic risks. In addition, the extract helped to improve relevant metabolic profiles in this high-risk population.
24173365 Impact of pre-existing chronic conditions on age differences in sickness absence after a m 2014 Mar OBJECTIVES: This study aims to examine the extent to which a greater prevalence of pre-existing chronic conditions among older workers explains why older age is associated with longer duration of sickness absence (SA) following a musculoskeletal work-related injury in British Columbia. METHODS: A secondary analysis of workers' compensation claims in British Columbia over three time periods (1997-1998; 2001-2002, and 2005-2006), the study comprised 102 997 and 53 882 claims among men and women, respectively. Path models examined the relationships between age and days of absence and the relative contribution of eight different pre-existing chronic conditions (osteoarthritis, rheumatoid arthritis, hypertension, coronary heart disease, diabetes, thyroid conditions, hearing problems, and depression) to this relationship. Models were adjusted for individual, injury, occupational, and industrial covariates. RESULTS: The relationship between age and length of SA was stronger for men than women. A statistically significant indirect effect was present between older age, diabetes, and longer days of SA among both men and women. Indirect effects between age and days of SA were also present through osteoarthritis, among men but not women, and coronary heart disease, among women but not men. Depression was associated with longer duration of SA but was most prevalent among middle-aged claimants. Approximately 70-78% of the effect of age on days of SA remained unexplained after accounting for pre-existing conditions. CONCLUSIONS: Pre-existing chronic conditions, specifically diabetes, osteoarthritis and coronary heart disease, represent important factors that explain why older age is associated with more days of SA following a musculoskeletal injury. Given the increasing prevalence of chronic conditions among labor market participants (and subsequently injured workers) moderate reductions in age differences in SA could be gained by better understanding the mechanisms linking these conditions to longer durations of SA.
23808492 A role for interleukin-17A in modulating intracellular survival of Mycobacterium bovis bac 2013 Nov Interleukin 17A IL-17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL-17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL-17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in RAW264.7 murine macrophages. We observed that IL-17A pre-treatment for 24 hr was able to synergistically enhance BCG-induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose- and time-dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL-17A was found to specifically enhanced BCG-induced phosphorylation of Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG-infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL-17A-enhanced NO production in BCG-infected macrophages. We further demonstrated that IL-17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO-dependent killing mechanism. In conclusion, our study revealed an anti-mycobacterial role of IL-17A through priming the macrophages to produce NO in response to mycobacterial infection.
23750281 A binding-site barrier affects imaging efficiency of high affinity amyloid-reactive peptid 2013 Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar α helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the α helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant "binding site barrier" effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits.
23651618 Comparative proteome analysis of Tumor necrosis factor α-stimulated human Vascular Smooth 2013 May 7 BACKGROUND: Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin. RESULTS: To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI-TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway. CONCLUSION: Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent.
23575550 The effect of folate supplementation on methotrexate efficacy and toxicity in psoriasis pa 2013 Jun BACKGROUND: Methotrexate (MTX) is an effective treatment for psoriasis but its use is limited by its toxicity. Folate supplementation can be used to reduce the adverse effects of MTX, though this may impact efficacy. The frequency of folic acid supplementation is not well characterized. PURPOSE: The objective of this study was to review the literature involving the use of folate in patients (in particular those with psoriasis) treated with MTX and analyze trends in folic acid use. METHODS: We searched PubMed from 1 May 1989 through 1 April 2012 using the terms 'folic acid,' 'folinic acid,' 'folate,' 'supplementation,' and 'methotrexate.' We also used the National Ambulatory Medical Care Survey (NAMCS) database to collect data regarding trends in MTX use and folic acid supplementation by physicians in the USA from 1993 through 2009. We assessed data including the number of MTX visits, rate of folic acid use, diagnoses, physician specialty, and demographics of patients. We used linear regression to analyze the change in folic acid use over time. RESULTS: Twenty-six published trials were included addressing folic acid supplementation with MTX. The majority found a benefit to folic acid supplementation, but there were only seven studies in psoriasis. Dermatologists were among the highest prescribers of MTX, and psoriasis was commonly treated with MTX. Folic acid supplementation significantly increased over this time period (p < 0.0001). However, dermatologists ranked lowest for their folate use, co-prescribing folate to only 9.1 % of MTX-treated patients. LIMITATIONS: In contrast to rheumatoid arthritis, there is a scarcity of literature describing the effect of folate on MTX toxicity and efficacy in psoriasis patients. NAMCS data only included outpatient visits to non-federally employed physicians, and there is the possibility of healthcare providers not documenting over-the-counter folic acid usage. Lastly, doses of MTX and folic acid were not recorded in the database. CONCLUSION: Dermatologists were the least likely specialists to supplement MTX with folic acid. The evidence for supplementation of folic acid is mixed. The literature confirms a reduction in the adverse effects of MTX but less strongly that there may be a reduction in efficacy too. Keeping in mind the potential for folate to reduce MTX efficacy, folic acid supplementation should be considered in MTX-treated patients.
23569358 Development of primary malignant melanoma during treatment with a TNF-α antagonist for se 2013 It is recognized that immunosuppression may lead to reduced immune surveillance and tumor formation. Because of the immunosuppressive properties of tumor necrosis factor (TNF)-alpha (TNF-α) antagonists, it is plausible that these biologics may increase the risk of the occurrence of malignancies or the reactivation of latent malignancies. TNF-α antagonists have gained momentum in the field of dermatology for treating rheumatoid arthritis and psoriasis, and they have revolutionized the treatment of other inflammatory autoimmune diseases such as refractory Crohn's disease. However, there is accumulating evidence that TNF-α inhibitors slightly increase the risk of cancer, including malignant melanoma (MM). The authors herein report the case of a 54-year-old female patient who developed a primary MM during treatment with adalimumab for severe Crohn's disease resistant to successive medical therapies. The patient had been receiving this TNF-α blocker therapy for 3 years before the occurrence of MM. After wide surgical excision of the lesion and staging (based on Breslow thickness and Clark level), evaluation with a whole-body computed tomography scan was negative for metastatic disease. The long duration of the adalimumab therapy and the patient's lack of a predisposition to skin cancer suggest an association between anti-TNF-α drugs and melanocytic proliferation. The authors also review the literature on the potential association between anti-TNF regimens and the occurrence of malignancies such as melanocytic proliferations. There is a substantial hypothetical link between anti-TNF-α regimens such as adalimumab and the potential for cancers such as melanoma. However, the risk of malignancy with biological therapy remains to be established, and most of the relevant studies have lacked the statistical power and randomization required for large clinical trials. Further long-term controlled clinical trials and registries are required to investigate this potentially serious association.
23469378 2013 Feb OBJECTIVES: Specific objectives were to examine the following: (1a) how results of Bayesian mixed treatment comparison (MTC) methods compare with several commonly considered frequentist indirect methods; (1b) how Bayesian MTC methods perform for different evidence network patterns; (2) how meta-regression can be used with Bayesian MTC meta-analysis to explore heterogeneity; and (3) how findings of Bayesian MTC meta-analyses compare for different numbers of studies and different network pattern assumptions. For objectives 1 and 2, we aimed to conduct case studies using data from two recent comparative effectiveness reviews (CERs). For objective 3, we aimed to use simulated data. METHODS: For objectives 1 and 2, we used data from CERs that examined second-generation antidepressants (SGAs) and biologic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA). For objective 1, we compared results of Bayesian MTC methods with those of three frequentist indirect methods: meta-regression, the Bucher method, and logistic regression for dichotomous and continuous outcomes. For objective 2, we conducted two types of meta-regression. One explored subgroup effects with a binary covariate to assess whether efficacy of SGAs differs between older adults (≥55 years) and adults of any age. The other explored a continuous covariate to assess whether treatment efficacy varies by disease duration of RA. For objective 3, we used simulated data to examine the Bayesian MTC method's ability to produce valid results for two data scenarios when varying numbers of studies were available for each comparison for various network patterns. RESULTS: Bayesian MTC methods permitted the calculation of results for more comparisons of interest than frequentist meta-regression or the Bucher method (when applied as they would typically be used). When comparisons were calculated, the findings generally agreed but differed for a small proportion (less than 10%) of comparisons. Regarding precision, logistic regression produced the most precise estimates, followed by the Bayesian MTC method. Our meta-regressions found a trend toward lesser efficacy for SGAs in older adults and a trend toward greater efficacy of biologic DMARDs for those with greater mean disease duration. Our simulations supported the validity of Bayesian MTC methods for star and ladder network patterns but raised some concerns about one closed loop (and possibly loop) network patterns. Simulations generally found similar probabilities for which drug was the best treatment for scenarios when only 1 study was available for each comparison and those when more studies (2, 3, 5, or 10) were available; precision increased as the number of available studies increased. CONCLUSIONS: Bayesian MTC methods offer several advantages over frequentist indirect methods, including the ability to produce results for all comparisons of interest in a single analysis. Results of Bayesian MTC methods and those of frequentist indirect methods may differ for a small proportion of comparisons, which could lead to differences in conclusions when using different methods. Our findings raise some concerns about the validity of the results of Bayesian MTC methods for certain network patterns. Further research is needed to explore additional real-world datasets and simulated data to determine if our findings are reproducible or generalizable and to better understand the validity of Bayesian MTC methods for various scenarios.
23170908 Graves' hyperthyroidism and moderate alcohol consumption: evidence for disease prevention. 2013 Jul BACKGROUND: We recently demonstrated that moderate alcohol consumption is associated with a considerable reduction in the risk of autoimmune hypothyroidism, similar to findings in other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. We aimed to study a possible association between alcohol intake and autoimmune Graves' hyperthyroidism. DESIGN: This is a population-based, case-control study. METHODS: In a well-defined Danish population (2,027,208 person-years of observation), we prospectively identified patients with new overt thyroid dysfunction and studied 272 patients with Graves' hyperthyroidism. For each patient, we recruited four age-gender-region-matched controls with normal thyroid function (n = 1088). MEASUREMENTS: Participants gave detailed information on current and previous alcohol intake as well as other factors to be used for analyses. The association between alcohol intake and development of hyperthyroidism was analysed in conditional multivariate Cox regression models. RESULTS: Graves' patients had a lower reported alcohol consumption than controls (median units of alcohol (12 g) per week: 2 vs 4, P < 0·001). In a multivariate regression model, alcohol consumption was associated with a dose-dependent reduction in risk for development of overt Graves' hyperthyroidism. Odds ratios (95% confidence interval) compared with the reference group with a recent (last year) consumption of 1-2 units of alcohol per week were as follows: 0 units/week 1·73 (1·17-2·56), 3-10 units/week 0·56 (0·39-0·79), 11-20 units/week 0·37 (0·21-0·65), ≥21 units/week 0·22 (0·08-0·60). Similar results were found for maximum previous alcohol consumption during a calendar year. No interaction was found with the type of alcohol consumed (wine vs beer), smoking habit, age, gender or region of inhabitancy. CONCLUSIONS: Moderate alcohol consumption is associated with a considerable reduction in the risk of Graves' disease with hyperthyroidism--irrespective of age and gender. Autoimmune thyroid disease seems to be much more dependent on environmental factors than hitherto anticipated.
23127799 Characterization of fibrinogen-like protein 2 (FGL2): monomeric FGL2 has enhanced immunosu 2013 Feb Fibrinogen-like protein 2 (FGL2), a novel effector molecule of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), mediates its suppressive activity through binding to low affinity Fcγ receptors expressed on antigen presenting cells (APCs). FGL2 has been implicated in the pathogenesis of viral hepatitis, xeno- and allotransplant rejection, and rheumatoid arthritis. Here we fully analyzed the structure-function relationships of recombinant murine FGL2 generated in COS-7 cells and identified the receptor binding domains. Native FGL2 exists as an oligomer with a molecular weight of approximately 260 kDa, while under reducing conditions, FGL2 has a molecular weight of 65 kDa suggesting that native FGL2 is composed of four monomers. By site-directed mutation, cysteines at positions 94, 97, 184 and 187, found in the coiled-coil domain were shown to be crucial for FGL2 oligomerization. Monomeric FGL2 had a lower affinity binding to APCs, but increased immunosuppressive activity compared to oligomeric FGL2. Deglycosylation demonstrated that sugar moieties are critical for maintaining solubility of FGL2. SWISS-MODEL analysis suggested that FGL2 has a similar tertiary structure with other members of the fibrinogen family such as fibrinogen and tachylectin. Mutational analysis of cysteine residues and Western blots suggested an asymmetric bouquet-shaped quaternary structure for oligomeric FGL2, resembling many pattern-recognition molecules in the lectin pathway of innate immunity. The functional motifs of FGL2 were mapped to the C terminal globular domain, using a peptide blockade assay. These results collectively define the biochemical and immunological determinants of FGL2, an important immunosuppressive molecule of Treg providing important insights for designing FGL2-related therapeutics.
23000338 Crosstalk between VEGF and novel angiogenic protein regulates tumor angiogenesis and contr 2013 Jan We have identified and characterized a novel proangiogenic glycoprotein (NAP) with molecular weight of 67 kDa from synovial fluid of rheumatoid arthritis patients. Proteomic analysis of the protein revealed 29% sequence coverage with maximum identity for human retinoblastoma binding protein 2. N-terminal amino acid sequence showed no identity to recently discovered protein sequences. NAP was also identified in both normal and tumor cell lines by Western blotting. NAP is a permeability factor as verified by miles permeability assay. The proangiogenic potential of NAP was identified using shell less CAM, rat cornea and tumor on CAM assays. NAP induces expression of VEGF and Flt-1 gene as verified by promoter reporter gene analysis. Further NAP induces proliferation of endothelial cells and formation of tube like structures. NAP is also involved in migration and invasion of tumor cells. Clinical data revealed the presence of NAP in breast cancer biopsies. We have developed monoclonal antibody (mAb), and specific ELISA, which confirmed the presence of NAP in the cytosol of tumor cells. The mAb effect was evaluated with established angiogenic assays. Further, we investigated the detailed mechanism by which NAP induces angiogenesis. NAP is phosphorylated by VEGF induced activation of MAPK and JNK pathways through VEGFR2 phosphorylation. NAP involves JNK pathway predominantly with further activation of NFκB in downstream processing of VEGF activation. Together these findings establish that NAP displays angiogenic properties and promotes efficient neovascularization both in vitro and in vivo models. These observations suggest that anti-NAP-mAb can be targeted for antiangiogenic therapy of cancer.