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ID PMID Title PublicationDate abstract
22161696 The therapeutic potential of epigenetics in autoimmune diseases. 2012 Feb Autoimmune diseases now include over 100 conditions and are estimated to affect over 20 million people in the United States or 5% of the world population with numerous geographical differences coined as geoepidemiology. Further, concordance rates in monozygotic twins are significantly higher compared to dizygotic sets while being significantly below 50% for most autoimmune diseases. These lines of evidence suggest that additional mechanisms are needed to link the individual susceptibility with the proposed chemical and infectious factors in the environment. Epigenetics may well constitute this missing link to include DNA methylation, histone changes, and microRNA which contribute to the epigenome characterizing specific diseases. Importantly, these epigenetic changes may be ideal targets for new personalized treatments as suggested by data in cancer. A number of chemical and physical factors, along with proposed infectious agents or aging, are involved in the etiopathogenesis of autoimmune diseases through epigenetic changes. The most prominent evidence on the association between environment and autoimmunity has been reported in systemic lupus erythematosus, but similar mechanisms were proposed in rheumatoid arthritis, systemic sclerosis, and type 1 diabetes.
21906426 Recommendations for the use of biologic therapy from the Italian Society for Rheumatology: 2011 May The advent of biological agents has provided further opportunities to treat resistant or relapsing rheumatic diseases, with robust data for rheumatoid arthritis and spondyloarthritis coming from randomised controlled trials. However there are data also on other rare inflammatory rheumatic diseases even if the evidence available may be heterogeneous and/or controversial. Another challenging scenario is represented by diseases that are not uncommon, but that may present with multiple manifestations and prove resistant to conventional therapies, thus requiring the use of biological agents. To assist physicians in making correct therapeutic choices in such cases, the Italian Society for Rheumatology (SIR) has developed specific recommendations for the use of biological agents in rare disease or for the off-label use of such agents in refractory inflammatory disorders.
21856169 Challenges and opportunities in targeting the costimulation pathway in solid organ transpl 2011 Jun Signaling through the costimulatory pathway is critical in the regulation of T cell activation. Abatacept, a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis, binds to CD80 and CD86 on antigen presenting cells, blocking the interaction with CD28 on T cells. Belatacept, a second generation CTLA4-Ig with 2 amino acid substitutions, has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen. This review will summarize the role of costimulation in T cell activation, detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation.
21826093 Pharmacogenetics: implications for therapy in rheumatic diseases. 2011 Aug 9 DMARDs not only improve the joint pain and swelling associated with rheumatoid arthritis (RA), but also slow down the joint damage associated with the disease. The efficacy of biologic therapies, introduced in the past decade for the treatment of RA, has been unequivocally established. Similarly, in addition to traditional drugs such as hydroxychloroquine, new biologic agents such as rituximab have been introduced for systemic lupus erythematosus in recent years. However, considerable variability occurs in the responses of patients to these therapies. Pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs, is a rapidly progressing field in rheumatology. Pharmacogenetic applications, particularly to the old vanguard DMARD, methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible. The pharmacogenetics of commonly used DMARDs and of biologic therapies are described in this Review.
21617283 A case of DiGeorge syndrome in Georgia. 2011 Apr Patient 6 - year- old boy, with history of recurrent otitis, cleft palate, was admitted to the hospital for fever, abdominal pain; He had high ESR,CRP, low T lymphocytes, VSD. Peritoneal fluid was positive for pseudomona aeroginoza. Diagnosis of DiGeorge syndrome was confirmed by further genetical study. Immune deficiencies should be considered when infections are severe, persistent resistant to standard treatment, or caused by opportunistic organisms. Treatments can often correct many of the critical and immediate problems associated with DiGeorge syndrome such as heart defects, calcium defects, poor immune system functions and cleft palate. People who had poor immune function as children due to small or missing thymus, may have an increased risk of autoimmune disorders, such as a rheumatoid arthritis and Graves disease. Because DiGeorge syndrome can result in so many disorders, a number of specialists should be involved in diagnosing specific conditions, recommending treatments and providing care.
20974590 Co-morbidity of migraine with somatic disease in a large population-based study. 2011 Jan INTRODUCTION: The aim of this study was to determine sex specific co-morbidity of migraine and its subtypes migraine without aura (MO) and migraine with aura (MA) with a number of common somatic diseases. SUBJECTS AND METHODS: In 2002, a questionnaire containing previously validated questions to diagnose migraine and its subtypes as well as questions regarding some somatic diseases was sent to 46,418 twins residing in Denmark and born between 1931 and 1982. The twins are representative of the whole Danish population and were used as such in the present study. RESULTS: We found that 21, 23 and 12 conditions were co-morbid with migraine, MA and MO, respectively. Co-morbid diseases included previously documented diseases: asthma, epilepsy and stroke as well as new conditions: kidney stone, psoriasis, rheumatoid arthritis and fibromyalgia. MA had more co-morbidities than MO and females more than males. CONCLUSIONS: Migraine occurs in 20-30% of several medical conditions. It should be diagnosed and treated along with the primary disease.
22294630 Comparative effectiveness and safety of biological treatment options after tumour necrosis 2012 Aug BACKGROUND: Optimal treatment for rheumatoid arthritis (RA) after inadequate response (IR) to tumour necrosis factor α inhibitors (TNFi) remains uncertain. OBJECTIVE: To compare the efficacy and safety of biological agents after TNFi-IR. METHODS: A systematic literature search was carried out using Medline and Cochrane databases, as well as http://www.clinicaltrials.gov, and bibliographies of the retrieved literature were searched by hand. Randomised, placebo-controlled trials that enrolled patients with RA with TNFi-IR were included and American College of Rheumatology (ACR) response as primary efficacy outcome and adverse events (AEs), serious adverse events (SAEs) and serious infections (SIs) as safety measures were extracted. An indirect meta-analysis with pairwise comparisons of efficacy and safety data was then carried out using ORs or risk differences (RDs) in a random effects model. RESULTS: In four randomised controlled trials with 24 weeks' follow-up, direct comparisons of abatacept, golimumab, rituximab and tocilizumab versus placebo showed statistically significant mean ORs of 3.3-8.9 for ACR20, 5.5-10.2 for ACR50 and 4.1-13.5 for ACR70. Risks of AEs, SAEs and SIs versus placebo were non-significant. Indirect pairwise comparisons of the four biological agents showed no significant differences in ACR50 and ACR70. Golimumab had a significantly lower OR (0.56-0.59) for ACR20 but significantly fewer AEs (RD 0.13-0.18). Efficacy after one versus multiple TNFi failures did not differ significantly between the different biological agents. CONCLUSION: In patients refractory to one or more TNFi, new biological agents provide significant improvement with good safety. Lacking head-to-head trials, indirect meta-analysis enables a comparison of effectiveness and safety of biological agents with each other and shows that all biological agents have similar effects.
21471444 The tyrosine kinase BMX is an essential mediator of inflammatory arthritis in a kinase-ind 2011 May 15 Inflammatory cytokines like TNF play a central role in autoimmune disorders such as rheumatoid arthritis. We identified the tyrosine kinase bone marrow kinase on chromosome X (BMX) as an essential component of a shared inflammatory signaling pathway. Transient depletion of BMX strongly reduced secretion of IL-8 in cell lines and primary human cells stimulated by TNF, IL-1β, or TLR agonists. BMX was required for phosphorylation of p38 MAPK and JNK, as well as activation of NF-κB. The following epistasis analysis indicated that BMX acts downstream of or at the same level as the complex TGF-β activated kinase 1 (TAK1)-TAK1 binding protein. At the cellular level, regulation of the IL-8 promoter required the pleckstrin homology domain of BMX, which could be replaced by an ectopic myristylation signal, indicating a requirement for BMX membrane association. In addition, activation of the IL-8 promoter by in vitro BMX overexpression required its catalytic activity. Genetic ablation of BMX conferred protection in the mouse arthritis model of passive K/BxN serum transfer, confirming that BMX is an essential mediator of inflammation in vivo. However, genetic replacement with a catalytically inactive BMX allele was not protective in the same arthritis animal model. We conclude that BMX is an essential component of inflammatory cytokine signaling and that catalytic, as well as noncatalytic functions of BMX are involved.
21439785 Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease 2011 May The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases.
22517002 [Analysis of clinical features and the outcome in 91 cases of mixed connective tissue dise 2012 Apr 18 OBJECTIVE: To investigate the clinical features and prognosis of mixed connective tissue disease (MCTD). METHODS: Clinical, laboratory and instrumental examination information of 91 patients with MCTD,who were diagnosed between 1990 to 2008 in Peking University People's Hospital, were collected and analyzed retrospectively. These patients were following-up, and different outcoms compared. RESULTS: The most common manifestations of MCTD patients were Raynaud phenomenon, arthralgia, arthritis, fever, acratia, positivities of antinuclear antibodies (anti-ANA) and ribosenuclear protein antibodies (anti-RNP), which were 94.5%,78%,46.2%,48.4%,53.9%,100% and 100%, respectively.Six patients died, and 22 patients were lost in the follow-up after discharge. Among the remaining 63 patients, 8 developed into systemic lupus erythomatosus (SLE), and 2 into antineutrophil cytoplasmic antibodies-associated vasculitis (AAV), 1 into primary Sjogren's syndrome (pSS), and 2 into rheumatoid arthritis (RA) at one to six years after diagnosis of MCTD. The patients who initially manifested as alopecia, proteinuria, thrombocytopenia, low complement were more likely to develop into SLE. CONCLUSION: MCTD can develop into various autoimmune diseases, such as SLE, pSS, RA, AAV. Some clinical features can probably predict future outcomes.
22358068 Application of autologous stem cell transplantation in various adult and pediatric rheumat 2012 Apr In the past 15 years, more than 1,500 patients worldwide have received a hematopoietic stem cell transplant, mostly autologous, as treatment for a severe autoimmune disease (AD). A recent retrospective analysis of 900 patients showed that the majority had multiple sclerosis, systemic sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA; n = 65) and idiopathic cytopenic purpura. An overall 85% 5-year survival and 43% progression-free survival was seen, with 100-day transplant-related mortality (TRM) ranging between 1% (RA) and 11% (SLE and JIA). Around 30% of patients in all disease subgroups had a complete response, despite full immune reconstitution. In many patients, morphological improvement was documented beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of three ongoing large prospective, randomized, controlled trials will allow modification of the protocols to reduce the high TRM, which relates to regimen intensity, age of patient, and comorbidity. Multipotent mesenchymal stromal cells (MSCs), including autologous MSCs, have recently been tested in various ADs, exploiting their immune-modulating properties and apparent low acute toxicity. Despite encouraging small phase I/II studies, no positive data from randomized, prospective studies are as yet available in the peer-reviewed literature.
20238219 Transient osteoporosis of the hip: successful treatment with teriparatide. 2012 May A 62-year-old man presented with a 2-month history of increasing pain in the left hip. Magnetic resonance imaging (MRI) showed bone marrow edema (BME) of the left femur, dual energy X-ray absorptiometry (DXA) showed osteopenia at the same level, whereas pelvis X-rays failed to show any objective findings. After ruling out other possible causes of BME such as aseptic osteonecrosis, infectious arthritis, primary or metastatic malignancy, tuberculosis, osteomyelitis, rheumatoid arthritis, and seronegative spondyloarthropathies, a diagnosis of transient osteoporosis of the hip (TOH) was made, and treatment with teriparatide at a daily dose of 20 μg was started and continued for 4 weeks. Disappearance of the symptoms and normalization of MRI were obtained.
23281743 Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in aut 2012 Anti-CD20 therapy using rituximab directly targeting B cells has been approved for treatment of non-Hodgkin lymphoma, rheumatoid arthritis and anti-neutrophil cytoplasmic antibody-associated vasculitides and has led to reappreciation of B-lineage cells for anti-rheumatic treatment strategies. Moreover, blocking B-cell activating factor with belimumab, a drug that is licensed for treatment of active, seropositive systemic lupus erythematosus (SLE), represents an alternative, indirect anti-B-cell approach interfering with proper B-cell development. While these approaches apparently have no substantial impact on antibody-secreting plasma cells, challenges to improve the treatment of difficult-to-treat patients with SLE remain. In this context, anti-CD19 antibodies have the promise to directly target autoantibody-secreting plasmablasts and plasma cells as well as early B-cell differentiation stages not covered by anti-CD20 therapy. Currently known distinct expression profiles of CD19 by human plasma cell subsets, experiences with anti-CD19 therapies in malignant conditions as well as the rationale of targeting autoreactive plasma cells in patients with SLE are discussed in this review.
23136551 Targeting interleukin-6: all the way to treat autoimmune and inflammatory diseases. 2012 Interleukin (IL)-6, a cytokine featuring redundancy and pleiotropic activity, contributes to host defense against acute environmental stress, while dysregulated persistent IL-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases. Targeting IL-6 is thus a rational approach to the treatment of these diseases. Indeed, clinical trials of tocilizumab, a humanized anti-IL-6 receptor antibody have verified its efficacy and tolerable safety for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for treatment of these diseases. Moreover, a considerable number of case reports and pilot studies of off-label use of tocilizumab point to the beneficial effects of tocilizumab for a variety of other phenotypically different autoimmune and chronic inflammatory diseases. Elucidation of the source of IL-6 and of mechanisms through which IL-6 production is dysregulated can thus be expected to lead to clarification of the pathogenesis of various diseases.
23001805 Obliterative (constrictive) bronchiolitis. 2012 Oct Obliterative bronchiolitis (OB) (formerly termed bronchiolitis obliterans), is a rare fibrotic disorder involving terminal and respiratory bronchioles. The term constrictive bronchiolitis is synonymous with OB. Clinically, OB is characterized by progressive (often fatal) airflow obstruction, the absence of parenchymal infiltrates on chest radiographs, a mosaic pattern of perfusion on high-resolution computed tomographic scan, poor responsiveness to therapy, and high mortality rates. Most cases of OB occur in the context of a specific risk factor. Currently, most cases of OB occur in lung transplant recipients with chronic allograft rejection or hematopoietic stem cell transplant (HSCT) recipients with graft versus host disease (GVHD). Other causes of OB include connective tissue disease (CTD) (particularly rheumatoid arthritis); lower respiratory tract infections; inhalation injury; exposure or inhalation of toxic fumes, metals, dusts, particulate matter, or pollutants; occupational exposures; drug reactions; consumption of uncooked leaves of Sauropus androgynus; chronic hypersensitivity pneumonia; diffuse neuroendocrine cell hyperplasia; miscellaneous. When no cause is identified, the term cryptogenic obliterative bronchiolitis is used. This review discusses the salient clinical, radiographic, and histological features of OB and presents a management approach.
22452603 Antagonizing IL-6 in ankylosing spondylitis: a short review. 2012 Aug 1 Ankylosing spondylitis (AS) is a chronic inflammatory disorder with predilection for the axial skeleton, leading to progressive restricted mobility and deformity of the spine. The fundamental mechanism involves autoimmunity orchestrated by T cells. Similar to other rheumatic diseases, the complex interplay of cytokines such as tumour necrosis factor alpha, interleukin-6 (IL 6) and interleukin-10 (IL 10) has been implicated in the pathogenesis of the disease. Despite extensive research over the past decades, the treatment options for AS, are limited. Non steroidal antiinflammatory drugs are the first line of therapy, whereas anti TNF drugs are administered for refractory cases which fail to respond to the treatment. There have been conflicting views on the correlation of IL 6 with disease activity in AS. As such, the debate on the role of anti IL6 in AS is still ongoing. Anti IL 6 such as tocilizumab and siltuximab have proven efficacy based on the large randomized controlled trials. The Food and Drug Administration (FDA) has approved these drugs for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis. Researchers have adventurously experimented anti IL 6 therapy in AS but the conclusions made were not consolidated into international guidelines or consensus statement for clinical practice. In the present review, we explore the role of anti IL6 in the treatment of AS based on the cumulative evidence over recent years.
22185278 Measurement of methotrexate polyglutamates in human erythrocytes by ion-pair UPLC-MS/MS. 2011 Dec BACKGROUND: Low-dose methotrexate is used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, but its effectiveness greatly varies between individuals. Therapeutic drug monitoring of intracellular methotrexate metabolites, the γ-polyglutamates (MTXGlu(n)), in human erythrocytes has shown promise in providing a basis for individualization of therapy. RESULTS: This work presents expedient methodology for the analysis of MTXGlu(1-7) in human erythrocytes by ion-pair UPLC with detection by tandem MS (UPLC-ESI-MS/MS). The use of N,N-dimethylheptylamine as an ion-pair agent was found to be favorable over others. Thermal extraction of erythrocyte lysates provides a simple one-step extraction procedure. The entire chromatographic run time is 6 min and the assay was validated within the therapeutic range of these metabolites CONCLUSION: The developed sample preparation procedure in combination with ion-pair UPLC-ESI-MS/MS analysis allowed for expedient quantitation of MTXGlu(1-7) in human erythrocytes. The rapid analysis time would enable therapeutic drug monitoring of MTXGlu(1-7) in the clinic.
21787439 MicroRNAs in systemic rheumatic diseases. 2011 Jul 13 MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNAs about 21 nucleotides in length. miRNAs have been shown to regulate gene expression and thus influence a wide range of physiological and pathological processes. Moreover, they are detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. The role of miRNAs is evident in various malignant and nonmalignant diseases, and there is accumulating evidence also for an important role of miRNAs in systemic rheumatic diseases. Abnormal expression of miRNAs has been reported in autoimmune diseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. miRNAs can be aberrantly expressed even in the different stages of disease progression, allowing miRNAs to be important biomarkers, to help understand the pathogenesis of the disease, and to monitor disease activity and effects of treatment. Different groups have demonstrated a link between miRNA expression and disease activity, as in the case of renal flares in lupus patients. Moreover, miRNAs are emerging as potential targets for new therapeutic strategies of autoimmune disorders. Taken together, recent data demonstrate that miRNAs can influence mechanisms involved in the pathogenesis, relapse, and specific organ involvement of autoimmune diseases. The ultimate goal is the identification of a miRNA target or targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the development of disease.
21840737 Nonunion after arthrodesis of the first metatarsal-phalangeal joint: a systematic review. 2011 Nov Arthrodesis of the first metatarsal-phalangeal joint (MTPJ) has been proposed for treatment of first MTPJ pathology because of the perceived safety and efficacy. Nonunion of the arthrodesis site has been purported as a common complication. The author undertook a systematic review of the electronic databases and other relevant sources to identify material relating to the incidence of nonunion and other complications after arthrodesis of the first MTPJ. In an effort to procure the highest quality studies available, the studies were eligible for inclusion only if they involved patients undergoing arthrodesis of the first MTPJ using modern osteosynthesis techniques (1980 onward time restriction), included a minimum of 30 feet in the publication, and evaluated patients at a mean follow-up of ≥12 months' duration. The studies were also required to include details of any complications requiring surgical intervention, had not primarily involved only rheumatoid arthritis as an indication, and had not involved the use of a structural bone graft. A total of 37 studies involving a total of 2,818 first MTPJ arthrodesis procedures were identified that met the inclusion criteria. The weighted mean age of the patients was 59.3 years, the follow-up was 34.3 months, and the union time was 64.3 days. For those studies that specifically mentioned the indications for first MTPJ arthrodesis, 2,656 joints were included as follows: severe hallux valgus (47.2%), hallux rigidus (32%), rheumatoid arthritis (11.5%), and revision of failed surgery (9.3%). Osteosynthesis involved 3 main configurations: compression screws, dorsal plate and screws, or staples. The overall nonunion incidence was 5.4% (153 of 2,818), with symptomatic nonunion occurring in 32.7% (50 of 153) of all nonunions (1.8% total incidence; 50 of 2,818). The overall incidence of malunion was 6.1% (39 of 640), with dorsal malunion accounting for 87.1% (34 of 39). The overall incidence of hardware removal was 8.5% (69 of 817). The historical comment that nonunion occurs in approximately 10% of attempted first MTPJ arthrodesis procedures is inaccurate. The incidence of malunion and hardware removal is inappropriately high, and efforts to determine effective methods of decreasing their incidence should be undertaken. Additionally, there is still a need for methodologically sound prospective cohort studies focusing on the use of arthrodesis of the first MTPJ for purely severe hallux valgus and specific grades of hallux rigidus, as well as specific forms of osteosynthesis, because this has only been infrequently reported in small series.
21905594 [Predictors of self-rated health of citizens on the territory of endangered political secu 2011 Mar INTRODUCTION: Self-rated health is generally accepted by researchers as a valid measure of health status. The aims of the study were to investigate how the adult inhabitants of northern Kosovska Mitrovica described their health and which variables were the predictors of self-rated health status among that population. METHOD: The research was done as a cross-sectional study on the representative sample of 318 adult inhabitants of northern Kosovska Mitrovica in 2006. The instrument of research was a questionnaire containing questions about self-rated health and demographic and socio-economic characteristics, mental health, social interaction, possibilities of performing everyday activities, health behaviour and habits, diseases and injuries, utilization of health care service. The independent variables were defined through the factor analysis taken from these groups of questions. The multivariate stepwise linear regression was done to determine the correlation between self-rated health and independent variables. RESULTS: More than half of the respondents (54.7%) assessed their health as good or very good. The predictors of self-rated health were gender, mood problems, myocardial infarction, chronic bronchitis, psychic and neurotic disorders, rheumatic arthritis, high blood sugar, utilization of private gynaecologist service and paying for diagnostic service. CONCLUSION: Most of the respondents from northern Kosovska Mitrovica assessed their own health as good or very good. Bad and very bad health was significantly associated with females, problems with mood, myocardial infarction, chronic bronchitis, psychic or neurotic disorders, rheumatoid arthritis and high blood sugar. Good and very good health was significantly associated with utilization of private gynaecologist service and paying for diagnostic service.