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ID PMID Title PublicationDate abstract
22580894 Data quality challenges in systemic lupus erythematosus trials: how can this be optimized? 2012 Aug Major scientific advances in basic science, pharmacology, and translational medicine have allowed the discovery of new molecular targets whose manipulation by new chemical entities has led to treatments for inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Development of new agents for systemic lupus erythematosus (SLE) has lagged, however, because the protean manifestations of SLE present challenges for measuring therapeutic effects in a consistent manner. Composite end points combining several Disease Activity Indices (DAIs) are being used in ongoing global studies, but the uniform application of these complex DAIs across large numbers of clinical sites has proven difficult. We describe herein approaches that are being utilized to facilitate collection, review, and analysis of the clinical measures utilizing independent central adjudication committees.
22559272 Exosome-delivered microRNAs of "chromosome 19 microRNA cluster" as immunomodulators in pre 2012 Jul 2 BACKGROUND: Structural rearrangements of chromosomal band 19q13 are a non-random cytogenetic abnormality in thyroid adenomas and adenomatous goiters and lead to an expression of miRNAs of the chromosome 19 microRNA cluster C19MC. Normally, expression of these miRNAs is silenced except for embryonic stem cells and the placenta where they represent the majority of miRNAs not only in the trophoblast but also in exosomes derived from it. PRESENTATION OF THE HYPOTHESIS: We have advanced the hypothesis that as part of the feto-maternal communication miRNAs of C19MC serve immunomodulatory functions in the placenta and confer a growth advantage to thyroid nodules by protecting them against autoimmune attacks. More precisely, the exosomes containing these miRNAs may specifically target immune cells in their local environment as well as systemically by transferring their cargo to recipient cells. Within these target cells the transferred miRNAs can interact with mRNAs of the recipient cells thereby suppressing their immune-specific functions. TESTING THE HYPOTHESIS: Experiments used to demonstrate the immunomodulatory capacity of placenta-derived exosomes can be modified by transfecting the target cells with those miRNAs of C19MC represented in placental exosomes. IMPLICATIONS OF THE HYPOTHESIS: Mimics of C19MC-derived miRNAs might develop to useful drug candidates for the treatment of autoimmune disease as e.g. rheumatoid arthritis and Sjögren's syndrome and for the prevention of transplant rejection. In case of tumor entities with elevated expression of C19MC miRNAs these miRNAs may be interesting targets for treatment with appropriate antagonists.
22316789 Quantification of hand grasp force using a pressure mapping system. 2012 The goal of this study was to use a pressure sensor to measure the force distribution and contact area of the hand when gripping, pushing, and pulling a cylinder. Data was collected from 10 subjects with no hand impairments and from 1 subject with rheumatoid arthritis (RA). Subjects grasped an aluminum cylinder wrapped with a Tekscan pressure sensor and performed each trial at 25%, 50%, and 100% maximum voluntary exertion. A relationship was found between increasing exertion and increasing hand area with increasing hand contact area. The force distribution maps showed the thenar region of the hand exerts the most force during pushing while the metacarpal joint line exerts the highest force during pulling. The third and fourth phalange were found to exert the highest phalange force during gripping. The force distribution maps from the RA subject showed higher thumb forces and distal phalange forces, relative to the entire phalange, compared to the non-impaired subjects. This suggests that the RA subject compensates for the lack of phalange function with the regions of the hand that still function. Future studies should sample individuals with a larger hand area range and sample more individuals with RA.
22054762 Biologics and infections: lessons from tumor necrosis factor blocking agents. 2011 Dec In the decade since tumor necrosis factor α (TNF-α) antagonists were first approved for clinical use, they have proven invaluable for the treatment of specific types of chronic inflammation. Currently licensed TNF blockers fall into two classes, monoclonal antibody (or antibody fragments) and soluble receptor. Although they are equally effective in rheumatoid arthritis and psoriasis, important differences have emerged with regard to efficacy in granulomatous inflammation and risks of granulomatous infections, particularly tuberculosis. This article focuses on recent studies that inform prevention and management of infections in this susceptible patient population.
21861088 Treatment of intractable skin ulcers caused by vascular insufficiency with allogeneic cult 2012 Mar Chronic leg ulcers have various causes and can be difficult to treat, although topical treatments, including basic fibroblast growth factor and PGE1, have been used. We applied an allogeneic cultured dermal substitute (CDS) to eight patients with intractable ulcers. The patients had various underlying diseases, including diabetes mellitus, systemic lupus erythematosus, antiphospholipid syndrome, necrobiosis lipoidica, stasis dermatitis, livedo vasculopathy, and rheumatoid arthritis. The CDS was prepared by seeding cultured human fibroblasts on a spongy matrix consisting of hyaluronic acid and atelocollagen. Good clinical results were achieved, as demonstrated by reepithelization, healthy granulation tissue formation, and a subsequent decrease in wound size. Daily dressing changes became unnecessary when the allogeneic CDS was used. Based on these results, we suggest that CDS may be useful for the treatment of intractable skin ulcers.
21417732 Biotherapeutic bioanalysis: a multi-indication case study review. 2011 Mar A thorough understanding of the structure and biology of a biotherapeutic is crucial to defining a suitable strategy for pharmacokinetic characterization in proof-of-concept disease models, toxicology species as well as the healthy and disease indication patient populations. This manuscript summarizes parameters that impact bioanalytical strategy for over 50 biotherapeutics indicated for the treatment of oncology, rheumatoid arthritis, allergy, multiple sclerosis, hematology, metabolism and infectious disease. We have addressed numerous therapeutic modalities including chimeric, humanized and fully human monoclonal antibodies, replacement proteins, peptides and fusion proteins, including polyethylene glycol and Fc fusions, as well as antibody-drug conjugates. With the rapid evolution of biotherapeutics over the last 20 years and the contraction of the pharmaceutical and biotechnology labor force, efficient workflow management becomes a crucial bioanalytical component. Thus, we have also addressed new technologies that have demonstrated either increased throughput or enhanced characterization, including Meso Scale Discovery, Gyrolab and affinity MS.
21357990 [Endothelial progenitor cells as a new marker of endothelial function with respect to risk 2011 Jan 3 The discovery of endothelial progenitor cells (EPC), over a decade ago, has refuted the previous belief that vasculogenesis only occurs during embryogenesis. The results of several studies revealed altered number and impaired function of EPC in hyperlipidemia, hypertension, diabetes, obesity as well as in rheumatoid arthritis. The population of developmental age is characterized by higher counts of EPC compared to adults. However, among young patients with chronic disorders that affect the vascular system, the number of EPC decreases. The reduced circulating concentration of EPC has become a surrogate marker of endothelial function and has been implicated in the pathogenesis of many vascular diseases. This article aims to review the biology and pathophysiology of EPC in the conditions of cardiovascular risk factors. The potential possibilities of increasing EPC number and function as well as the use of EPC in the treatment of vascular pathology will also be discussed.
20797713 Endometriosis and autoimmune disease: association of susceptibility to moderate/severe end 2011 Jan This study investigates the association of rheumatoid arthritis-associated single nucleotide polymorphisms in endometriosis. We found an association of CCL21 (rs2812378) and HLA-DRB1 (rs660895) with moderate to severe endometriosis.
22855957 Antinuclear Antibody, Rheumatoid Factor, and Cyclic-Citrullinated Peptide Tests for Evalua 2007 In response to a request from the public, a systematic review assessed the test performances of antinuclear antibody (ANA), rheumatoid factor (RF), and cyclic-citrullinated peptide (CCP) for pediatric systemic lupus erythematosus (pSLE) and juvenile idiopathic arthritis (JIA) among children (≤18 years) with undiagnosed musculoskeletal (MSK) pain. The systematic review included 28 clinical studies published from January 1960 to January 2010 and also characterized the prevalence and etiology of MSK pain in children. This summary is provided to inform discussions of options with patients and to assist in decisionmaking along with consideration of the values and preferences of patients and their caregivers; it should not be construed to represent clinical recommendations or guidelines. The full report is available at www.effectivehealthcare.ahrq.gov/anatest.cfm.
23207775 Co-administration of water containing magnesium ion prevents loxoprofen-induced lesions in 2012 Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200 µg/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14 d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.
22396044 A benzamide-linked small molecule NDMC101 inhibits NFATc1 and NF-κB activity: a potential 2012 Aug PURPOSE: Using receptor activator of NF-κB ligand (RANKL) induced osteoclast differentiation on RAW264.7 as a screening tool; we synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for rheumatoid arthritis. METHODS: Differentiation into osteoclast-like cells was examined by tartrate-resistant acid phosphatase (TRAP) staining and expression of osteoclast differentiation markers. Collagen-induced arthritis (CIA) mice were administered test articles by gavages to assess its efficacy. Then clinical, histological, and biochemical parameters were assessed to determine the effects of N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (NDMC101) on synovial inflammation and bone erosion by hematoxlin and eosin staining and Enzyme-linked immunosorbent assay (ELISA). RESULTS: NDMC101 markedly inhibited RANKL-induced formation of TRAP+ multinucleated cells in RAW264.7 and bone marrow macrophage cells (BMMs). Moreover, pit formation assay showed that NDMC101 significantly reduced the bone-resorbing activity of mature osteoclasts. In CIA mice, oral administration of NDMC101 reduced arthritic index and mitigated bone erosion. Serum TNF-α and IL-1β concentrations in these mice were decreased significantly at the higher dose of 62.5 mg/kg. CONCLUSIONS: Screening of our chemical library, our findings suggest that NDMC101 inhibits osteoclastogenesis which also ameliorates paw swelling and inflammatory bone destruction. Its efficacy is associated with the inhibition of such transcription factors as NF-κB and NFATc1 as well as multiple protein kinases, including p38, ERK, and JNK. There results guarantee further clinical tests of NDMC101 for its therapeutic potential in the treatment of inflammation-induced bone diseases.
23225089 Safety and efficacy of 0.1% clobetasone butyrate eyedrops in the treatment of dry eye in S 2013 May PURPOSE: To study the effects of a low administration rate and low concentration (0.1%) of clobetasone butyrate eyedrops in patients with Sjögren syndrome (SS).
 METHODS: This prospective, double-masked, randomized, placebo-controlled study included 40 subjects divided into 2 treatment groups: group 1 (2% polyvinylpyrrolidone eyedrops and placebo) and group 2 (2% polyvinylpyrrolidone and 0.1% clobetasone butyrate, 1 drop BID). The treatment lasted for 30 days, with visits at enrollment, baseline, day 15, day 30, and after 15 days of treatment discontinuation. At each visit, symptoms questionnaire, tear film break-up time, corneal fluorescein stain, lissamine green stain, conjunctival impression cytology for human leukocyte antigen-DR (HLA-DR) expression, intraocular pressure (IOP) measurement, and fundus examination were performed. 
 RESULTS: No changes in IOP or fundus examination were observed in either group at each time point. Group 1 patients showed at day 30 a statistically significant amelioration of symptoms and reduction of HLA-DR expression. No changes in other parameters were detected. Group 2 patients showed at day 15 a statistically significant improvement of corneal and conjunctival stain versus baseline values and group 1 at the same time; after 30 days the symptoms score was statistically significantly better than baseline values and group 1 at the same time. The HLA-DR expression and the epithelial cells area were statistically significantly reduced versus baseline and group 1 at the same time. 
 CONCLUSIONS: Anti-inflammatory therapy is critical for the treatment of SS dry eye. Clobetasone butyrate, at low dosage, proved to be safe and effective in treating this condition.
22382336 Detection of HTLV-1 in the labial salivary glands of patients with Sjögren’s syndrome: 2012 Apr OBJECTIVE: To examine whether patients with Sjögren's syndrome (SS) can be distinguished based on the expression of human T cell lymphotrophic virus type I (HTLV-1) and, if so, whether the subgroups differ in their clinical features and serological measures. METHODS: Polymerase chain reaction (PCR) and nested PCR were used to amplify viral DNA from peripheral blood mononuclear cells (PBMC) in 53 patients with SS, using primers from the HTLV-1 pX, p19, pol, and tax regions. Minor salivary gland biopsy specimens from 33 patients with SS were examined for the presence of HTLV-1 p19 or tax proteins immunohistochemically. The sociodemographic, glandular, and extraglandular manifestations, and laboratory findings including autoantibodies, complement, and immunoglobulin levels, were analyzed. RESULTS: The HTLV-1 tax gene was detected in PBMC samples from 2 of 53 patients (3.8%), whereas the HTLV-1 pX, p19, and pol genes were not expressed. As well, 100% of PBMC samples from 4 family members of patients in whom the tax gene was detected also expressed the tax gene. Immunohistochemical staining for HTLV-1 p19 and tax was seen in 10 out of 33 (30.3%) patients with SS each. Overall, 14 (42.4%) patients expressed HTLV-1 p19 or tax proteins, and they had lower rheumatoid factor and C3 levels (p = 0.015 and p = 0.005, respectively) and higher lymphocyte counts (p = 0.016). The prevalence of glandular and extraglandular manifestations did not differ between the HTLV-1-positive and negative patients. CONCLUSION: Our findings suggest that HTLV-1 in the salivary glands is involved in the pathogenesis of a subpopulation of SS, and HTLV-1-associated SS might have different immunological patterns than idiopathic SS.
22208658 Local activation and systemic dysregulation of T lymphocytes in Sjögren's syndrome. 2012 Aug T cells are implicated in both local and systemic pathophysiology of primary Sjögren's syndrome (PSS). Lymphocytic infiltrates in exocrine glands are dominated by CD4+ T cells, some contributing to ectopic lymphoid tissue, others, unusually, exhibiting cytotoxic potential. Cytokine secretion patterns are complex, with Th1 and Th17 components implicated in pathology. Circulating T cells exhibit phenotypes consistent with hyperactivation, cytokine imbalance, and homeostatic alterations; CD4 lymphopenia is recognized as a risk factor for developing lymphoma. Evidence of oligoclonal expansion is found locally and systemically. Functional alterations (e.g. cytokine secretion profile, migratory potential, target cell interactions) are less clearly defined. Attempts at T cell-targeted therapy of PSS have been limited, although therapy targeted at other arms of the immune response may also affect T cells. A better understanding of T-cell dysregulation in PSS is required in order to understand its contribution to disease, aid prognosis, and improve therapeutic interventions aimed at this aspect of the disease.
22126023 Laminin isoform profiles in salivary glands in Sjögren's syndrome. 2011 Five different laminin (LM) alpha, four LM-beta, and three LM-gamma chains form the 15-16 currently known approximately 400-900 kDa heterodimeric LM-monomers, which self-assemble in the lamina lucida of the basement membrane (BM) to a network, connected with nidogens and perlecans with the underlying type IV collagen network. In labial salivary glands (LSG), the structurally organizing/polarizing BM separates the tubuloacinar epithelium from the connective tissue stroma but plays regulatory roles as well. Tissue distribution of LM-alpha, -beta, and -gamma chains is described, and application of the known combinatorial rules allows some conclusions also on the corresponding distribution of the LM-trimers. Currently, known integrin (Int) and non integrin (e.g., dystroglycans and Lutheran blood group antigens) LM-receptors are described. LMs are regulated at transcriptional, translational, and posttranslational levels, together with the regulation of alternative splicing, binding partners (assembly), secretion, and degradation. In LSGs, LM-alpha1, -alpha2, and -alpha4 are only found in the acinar (not ductal) BM, LM-alpha4 also in the periductal/ interstitial stroma. Pattern recognition disclosed irregular expression in the acinar BM, suggesting some dynamic and/or regulatory role. It seems that in a female-dominant autoimmune exocrinopathy, Sjögren's syndrome (SS), LM-alpha1 and -alpha2 are decreased, together with their Int alpha1beta1 and alpha2beta1 receptors. Because LM-111/211-to-Int-alpha1beta1/alpha2beta1 interactions play a crucial role in the transdifferentiation of the intercalated duct progenitors to secretory acinar cells, acinar remodeling is impaired in SS. Disturbed hemidesmosomal Int alpha6beta4/LM-332 interactions in SS may lead to acinar cell anoikis. Interestingly, dehydroepiandrosterone (DHEA) prohormone and its intracrine androgenic dihydrotestosterone (DHT) end product upregulate at least Int alpha1beta1/alpha2beta1, whereas LM-alpha1 is upregulated by outside-in LM-111/211-to-Int-alpha1beta1/alpha2beta1 signaling. It seems that LM alterations precede the lymphocyte infiltration, suggesting that acinar BM-Int pathology, perhaps related to endo- and intracrine sex steroid metabolism, represents an early pathogenic phases in SS.
21414150 Autoimmune disease as a risk factor for globus pharyngeus: a cross-sectional epidemiologic 2011 Feb OBJECTIVE: To assess the prevalence and severity of globus-type symptoms in individuals who have a prior diagnosis of autoimmune disease. DESIGN: Cross-sectional questionnaire. PARTICIPANTS AND SETTING:   One hundred and nine patients with autoimmune disease (rheumatoid arthritis, seronegative spondarthritis, connective tissue disease, systemic vasculitis) and 41 patients with non-autoimmune disease (osteoarthritis/osteoporosis) attending a rheumatology tertiary referral clinic at Norfolk & Norwich University Hospitals NHS Foundation Trust. The results from this study were compared to previous published figures in patients with globus pharyngeus (n = 105) and normal population (n = 174). MAIN OUTCOME MEASURES: Glasgow Edinburgh Throat Scale questionnaire; Reflux Symptom Index; Anxiety/Depression Scale. RESULTS: Patients with autoimmune disease demonstrate a significantly higher prevalence for 5/10 symptoms on the Glasgow Edinburgh Throat scale score when compared to the non-autoimmune control group (P ≤ 0.01). This significant difference increases to 9/10 symptoms when compared to published results for the normal population (P = 0.01). No significant difference was found when comparing the autoimmune and non-autoimmune control group reflux symptom index (P = 0.64) or anxiety depression scale (P = 0.71). CONCLUSION: Patients with autoimmune disease have a significantly increased prevalence of globus symptoms when compared to the healthy population. A further prospective study is required to decipher the effect of pharmacotherapy as a possible causative factor.
22735757 Bucillamine inhibits CD40-mediated Akt activation and antibody production in mouse B-cell 2012 Sep The improvement of rheumatoid factor titers in patients with rheumatoid arthritis is one of the significant clinical effects of bucillamine (Buc). In this study, we investigated the effects of SA981, an active metabolite of Buc, and methotrexate (MTX) on CD40-mediated antibody production using mouse B-cell lymphoma, BCL1. SA981 significantly attenuated CD40-mediated antibody production in a concentration-dependent manner, but weakly affected cell proliferation. In contrast, MTX did not attenuate CD40-mediated antibody production until it had strongly inhibited cell proliferation at a concentration of 100 nM. CD40 signaling induced protein phosphorylation, including Akt phosphorylation, p38 mitogen-activated protein kinase (p38MAPK), and IκBα. SA981 at a concentration of 30 μM attenuated CD40-mediated Akt phosphorylation, but not p38MAPK or IκBα phosphorylation. MTX at a concentration of 100 nM did not affect CD40-mediated Akt, p38MAPK, or IκBα phosphorylation. Commercially available Akt inhibitor VIII significantly attenuated CD40-mediated IgM production at a concentration of 100 nM without significant inhibition of cell proliferation. These results suggest that SA981 inhibits CD40-mediated antibody production in mouse B-cell lymphoma, at least in part, by attenuation of Akt phosphorylation.
22336078 Chronic urticaria and autoimmunity: associations found in a large population study. 2012 May BACKGROUND: Chronic urticaria (CU) is a common disease in which most cases were considered to be idiopathic. Recent evidence indicates that at least a subset of cases of chronic idiopathic urticaria are autoimmune in origin. OBJECTIVE: We aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population. METHODS: Data on 12,778 patients given a diagnosis of CU by either allergy or dermatology specialists during 17 years in a large health maintenance organization in Israel were collected. For each patient, we collected information on diagnosis of major, well-defined autoimmune diseases and autoimmunity- and inflammatory-related serologic markers. Similar data were collected for a control group comprised of 10,714 patients who visited dermatologists, family physicians, or allergy specialists and had no indication of CU. RESULTS: Having CU was associated with an increased odds ratio for hypothyroidism, hyperthyroidism, and antithyroid antibodies. Female patients with CU had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the diagnosis of CU. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all significantly more prevalent in patients with CU. CONCLUSIONS: A strong association was found between CU and major autoimmune diseases. A common pathogenic mechanism is implied by the high prevalence of autoantibodies and the existence of a chronic inflammatory process expressed by the high mean platelet volume. These findings have implications for the diagnosis, management, and prognosis of patients with CU.
21887609 Cutting-edge issues in organ-specific autoimmunity. 2011 Oct There have been numerous methods and ways to classify autoimmune diseases. By far, the most traditional has been to separate immune-mediated pathology into organ-specific and organ-non-specific diseases. The classic systemic autoimmune diseases are, of course, rheumatoid arthritis and systemic lupus. The classic organ-specific autoimmune diseases have been autoimmune thyroiditis and autoimmune gastritis. However, as our understanding of the loss of tolerance has expanded, so has the long list of autoimmune diseases. In many cases, the distinction between organ-specific and organ-non-specific or systemic autoimmunity becomes a blur. In this issue, we discuss recent concepts in autoimmune pancreatitis, primary sclerosing cholangitis, Goodpasture's syndrome, myofasciitis, type I diabetes, polymyositis, autoimmune thyroid disease, IgA nephropathy, autoimmune uveitis, and ANCA-associated vasculitis. Common themes on both etiology and effector mechanisms are described throughout these papers with an attempt to provide a cutting-edge overview.
21210257 Role of ultrasound and other advanced imaging in the diagnosis and management of gout. 2011 Apr Imaging of gout with conventional radiography has been described since shortly after roentgenography was invented. Ultrasound (US) detects more erosions than conventional radiography in rheumatoid arthritis, and the same seems to be true for gout. MRI is being used to assess articular and periarticular masses, including gouty tophi. However, MRI findings in gout can lack specificity. Monosodium urate (MSU) tophi are very echogenic when US is used. Typical US features of gout include a double-contour sign or "urate icing." The double-contour consists of the hyperechoic bony contour and a parallel hyperechoic line of MSU crystals that deposit on the hypoechoic or anechoic hyaline cartilage. Tophi can have a "wet clumps of sugar" appearance, often surrounded by an anechoic halo. Tophi are closely related to the formation of erosions. If serum urate levels are lowered consistently below 6.0 mg/dL, the disappearance of MSU crystals can be observed sonographically.